Podcasts about cyclin

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Best podcasts about cyclin

Latest podcast episodes about cyclin

Oncotarget
Expression of Cyclin D1 in Penile Cancer

Oncotarget

Play Episode Listen Later May 15, 2024 3:36


BUFFALO, NY- May 15, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on May 14, 2024, entitled, “Cyclin D1 expression in penile cancer.” In this new study, researchers Wesliany Everton Duarte, Jaqueline Diniz Pinho, Syomara Pereira da Costa Melo, Denner Rodrigo Diniz Duarte, Juliana Martins da Guia Ribeiro do Carmo, André Salim Khayat, José Ribamar Rodrigues Calixto, Marcos Adriano Garcia Campos, Rita da Graça Carvalhal Frazão Correa, Antonio Machado Alencar Júnior, Antônio Augusto Lima Teixeira-Júnior, and Gyl Eanes Barros Silva from Federal University of Maranhão, State University of Maranhão, Federal University of Pará, São Paulo State University, and University of São Paulo analyzed the expression profile of cyclin D1 in patients with PC, and to determine possible correlations with clinical and histopathological features. “Regarding PC, however, few studies have assessed the role of cyclin D1, reinforcing the necessity for initiatives that aim to investigate its actual role in the pathophysiology of this disease. As such, the present study aimed to characterize the expression of cyclin D1 in patients with PC, and to determine possible correlations with the clinical and histopathological features of the disease.” A survey was conducted with 100 patients diagnosed with PC, who were treated at two reference hospitals in São Luís, Maranhão, Brazil, between 2013 and 2017. A review of clinical, epidemiological, and histopathological data was performed, Human Papillomavírus (HPV) DNA was detected using polymerase chain reaction (PCR) and cyclin D1 expression analysis was performed using immunohistochemical techniques. The data revealed that the absence of cyclin D1 expression was significantly associated with HPV-positive histological subtypes (p = 0.001), while its expression was associated with high-grade tumors (p = 0.014), histological subtype (p = 0.001), presence of sarcomatoid transformation (p = 0.04), and perineural invasion (p = 0.023). Patients with cyclin D1 expression exhibited lower disease-free survival compared to the cyclin D1-negative group, although the difference was not statistically significant. “The results suggest that cyclin D1 may be a potential biomarker for PC, especially for poorer prognosis.” DOI - https://doi.org/10.18632/oncotarget.28584 Correspondence to - Gyl Eanes Barros Silva - gyl.silva@ufma.br Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28584 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, immunohistochemistry, biomarkers, cyclin D1, penile neoplasms About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Oncotarget
GFH009: A Potent and Highly Selective CDK9 Inhibitor for the Treatment of Hematologic Malignancies

Oncotarget

Play Episode Listen Later Dec 27, 2023 3:32


BUFFALO, NY- December 27, 2023 – A new #research paper was #published in Oncotarget's Volume 14 on December 20, 2023, entitled, “The pharmacodynamic and mechanistic foundation for the antineoplastic effects of GFH009, a potent and highly selective CDK9 inhibitor for the treatment of hematologic malignancies.” To evade cell cycle controls, malignant cells rely upon rapid expression of select proteins to mitigate pro-apoptotic signals resulting from damage caused by both cancer treatments and unchecked over-proliferation. Cyclin-dependent kinase 9 (CDK9)-dependent signaling induces transcription of downstream oncogenes promoting tumor growth, especially in hyperproliferative ‘oncogene-addicted' cancers, such as human hematological malignancies (HHMs). In this new study, researchers Fusheng Zhou, Lili Tang, Siyuan Le, Mei Ge, Dragan Cicic, Fubo Xie, Jinmin Ren, Jiong Lan, and Qiang Lu from GenFleet Therapeutics Inc. and Sellas Life Sciences Group aimed to summarize current knowledge underlying the mechanism of action (MOA) of GFH009 and explain its robust anti-cancer activity. “Understanding GFH009's MOA allows for a more optimal clinical development path, given the potential for meaningful benefits in patients with hematological malignancies.” GFH009, a potent, highly selective CDK9 small molecule inhibitor, demonstrated antiproliferative activity in assorted HHM-derived cell lines, inducing apoptosis at IC50 values below 0.2 μM in 7/10 lines tested. GFH009 inhibited tumor growth at all doses compared to controls and induced apoptosis in a dose-dependent manner. Twice-weekly injections of GFH009 maleate at 10 mg/kg significantly prolonged the survival of MV-4-11 xenograft-bearing rodents, while their body weight remained stable. There was marked reduction of MCL-1 and c-MYC protein expression post-drug exposure both in vitro and in vivo. Through rapid ‘on-off' CDK9 inhibition, GFH009 exerts a proapoptotic effect on HHM preclinical models triggered by dynamic deprivation of crucial cell survival signals. “Our results mechanistically establish CDK9 as a targetable vulnerability in assorted HHMs and, along with the previously shown superior class kinome selectivity of GFH009 vs other CDK9 inhibitors, strongly support the rationale for currently ongoing clinical studies with this agent in acute myeloid leukemia and other HHMs.” DOI - https://doi.org/10.18632/oncotarget.28543 Correspondence to - Jiong Lan - jlan@genfleet.com Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28543 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, GFH009, CDK9, leukemia, cell cycle About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Oncotarget
CDK9 Inhibitors: A Promising Combination Partner in Treating Hematological Malignancies

Oncotarget

Play Episode Listen Later Aug 9, 2023 2:40


A new research perspective was published in Oncotarget's Volume 14 on August 7, 2023, entitled, “CDK9 INHIBITORS: a promising combination partner in the treatment of hematological malignancies.” In their new perspective, researchers Daniel Morillo, Gala Vega and Victor Moreno from Hospital Fundación Jiménez Díaz discuss Cyclin-dependent kinases (CDK) in hematological malignancies. CDKs belong to a family of serine/threonine kinases that need to form heterodimeric complexes with cyclins to perform their functions. These kinases are involved in multiple processes within cells, including cell cycle, apoptosis, transcription and differentiation. These kinases are often overexpressed in different malignancies, making them potential targets for new drugs. Most hematological malignancies are characterized by overexpression of certain cancer promoting genes, such as MYC, MCL1 and cyclin D1. Preclinical studies in animal models have shown that CDK9 inhibitors suppress the transcription of these anti-apoptotic and pro-survival proteins, and suggest their potential synergism with other drugs. In its first in-human trial, enitociclib demonstrated clinical activity in a small cohort of patients with high grade B lymphoma with MYC and BCL2 and/or BCL6 rearrangements, inducing complete responses in 2 of 7 subjects (29%) in monotherapy. “In summary, most hematological malignancies are characterized by overexpression of certain cancer promoting genes, such as MYC and MCL1. CDK9 inhibitors are relatively new drugs that inhibit transcription of these anti-apoptotic and pro-survival proteins.” DOI - https://doi.org/10.18632/oncotarget.28473 Correspondence to - Victor Moreno - victor.moreno@startmadrid.com Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28473 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, cyclin-dependent kinases (CDK), CDK9, hematological malignancies About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

PaperPlayer biorxiv cell biology
Cyclin A/cdk activity and FAM122A-dependent inhibition of PP2A-B55 are essential to trigger mitosis.

PaperPlayer biorxiv cell biology

Play Episode Listen Later Jun 22, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.20.545672v1?rss=1 Authors: Lacroix, B., Vigneron, S., Labbé, J. C., Pintard, L., Labesse, G., Castro, A., Lorca, T. Abstract: Entry into mitosis has been classically attributed to the activation of cyclin B/cdk1 amplification loop by a partial pool of this kinase that becomes active at the end of G2. However, how this pool is activated is still unknown. Here we discovered a new role of the recently identified PP2A-B55 inhibitor FAM122A in triggering mitotic entry. Accordingly, the depletion of the orthologue of FAM122A in C. elegans, prevents entry into mitosis in germline stem cells. Moreover, our data in Xenopus egg extract strongly supports that FAM122A29 dependent inhibition of PP2A-B55 could be the initial event promoting mitotic entry. The inhibition of this phosphatase allows the subsequent phosphorylation of first mitotic substrates by cyclin A/cdk resulting in cyclin B/cdk1 and Greatwall (Gwl) activation. However, interestingly, from Gwl activation, Arpp19/ENSA become phosphorylated and compete with FAM122A promoting its dissociation from PP2A-B55 and taking over its inhibition until the end of mitosis. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

The Bat Around
The Bat Around-May 13, 2023- Bob Haynie, Ryan Blake

The Bat Around

Play Episode Listen Later May 13, 2023 134:10


The Bat Around is back with another installment and boy do we have a lot to cover! Cyclin' Ceddy stole the show last night, homering in his final AB to capture the 7th cycle in Orioles history! But don't let that distract you from the fact that Kyle Bradish was a dog! Bob Haynie from 105.7 The Fan joins us at 11:40 to talk all things Orioles! Plus Take to Rake! That and more on The Bat Around!

PaperPlayer biorxiv cell biology
Cdk/Cyclin activity helps set mitotic centrosome size by influencing the centrosome growth rate and growth period

PaperPlayer biorxiv cell biology

Play Episode Listen Later Apr 26, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.25.538283v1?rss=1 Authors: Wong, S.-S., Wainman, A., Saurya, S., Raff, J. W. Abstract: Mitotic centrosomes assemble when centrioles recruit large amounts of pericentriolar material (PCM) around themselves in preparation for cell division. How the mitotic PCM grows to the correct size is unclear. In Drosophila syncytial embryos, thousands of mitotic centrosomes assemble in a common cytoplasm as the embryo proceeds through 13 rounds of near-synchronous nuclear division. During nuclear cycles (NCs) 11-13 these divisions gradually slow, and we find that mitotic centrosomes respond by reciprocally slowing their growth rate and increasing their growth period so that they grow to a consistent size at each cycle. This size homeostasis is enforced, at least in part, by the Cdk/Cyclin cell cycle oscillator (CCO). Moderate levels of CCO activity appear to initially promote centrosome growth by stimulating Polo/PLK1 recruitment to centrosomes, while higher levels of activity subsequently inhibit centrosome growth by phosphorylating centrosome proteins to decrease their centrosomal recruitment and/or maintenance as the embryos enter mitosis. Thus, the CCO initially promotes, and subsequently restricts, mitotic centrosome growth to help ensure that centrosomes grow to a consistent size. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv neuroscience
Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Apr 24, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.24.538049v1?rss=1 Authors: Castano, A., Silvestre, M., Wells, C. I., Sanderson, J. L., Ferrer, C. A., Ong, H. W., Lang, Y., Richardson, W., Silvaroli, J. A., Bashore, F. M., Smith, J. L., Genereux, I. M., Dempster, K., Drewry, D. H., Pabla, N. S., Bullock, A. N., Benke, T. A., Ultanir, S., Axtman, A. D. Abstract: Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD have indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3b, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3b activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3b activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3b. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces post-synaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated, key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity and human neuropathology. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv cell biology
Cyclin E/CDK2 and feedback from soluble histone protein regulate the S phase burst of histone biosynthesis

PaperPlayer biorxiv cell biology

Play Episode Listen Later Mar 18, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.17.533218v1?rss=1 Authors: Armstrong, C., Passanisi, V. J., Ashraf, H. M., Spencer, S. L. Abstract: Faithful DNA replication requires that cells fine-tune their histone pool in coordination with cell-cycle progression. Replication-dependent histone biosynthesis is initiated at a low level upon cell-cycle commitment, followed by a burst at the G1/S transition, but it remains unclear how exactly the cell regulates this change in histone biosynthesis as DNA replication begins. Here, we use single-cell timelapse imaging to elucidate the mechanisms by which cells modulate histone production during different phases of the cell cycle. We find that CDK2-mediated phosphorylation of NPAT at the Restriction Point triggers histone transcription, which results in a burst of histone mRNA precisely at the G1/S phase boundary. Excess soluble histone protein further modulates histone abundance by promoting the degradation of histone mRNA for the duration of S phase. Thus, cells regulate their histone production in strict coordination with cell-cycle progression by two distinct mechanisms acting in concert. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv neuroscience
Generation of adult hippocampal neural stem cells occurs in the early postnatal dentate gyrus and depends on cyclin D2

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Dec 5, 2022


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.05.518892v1?rss=1 Authors: Pastor-Alonso, O., Syeda Zahra, A., Kaske, B., Garcia-Moreno, F., Tetzlaff, F., Bockelmann, E., Grunwald, V., Martin-Suarez, S., Riecken, K., Witte, O. W., Encinas, J. M., Urbach, A. Abstract: In the hippocampus, lifelong neurogenesis is maintained by a pool of multipotent adult neural stem cells (aNSCs) residing in the subgranular zone of the dentate gyrus (DG). Yet, the mechanisms guiding the transition of NSCs from developmental to adult remain unclear. By using nestin-reporter mice deficient for D2, a cyclin expressed mainly postnatally, we show that the aNSC pool is established through D2-dependent proliferation during the first two weeks of life. The absence of D2 allows the normal development of the DG until birth but prevents the postnatal formation of radial glia-like aNSCs. Additionally, retroviral fate mapping demonstrates that aNSCs are born on-site from precursors located in the DG shortly after birth. Altogether, our data suggest that aNSCs are a population distinct from developmental NSCs and thus imply that adult hippocampal neurogenesis is not a mere continuation of development. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv cell biology
Immortalized bovine satellite cells for cultured meat applications

PaperPlayer biorxiv cell biology

Play Episode Listen Later Dec 3, 2022


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.02.518927v1?rss=1 Authors: Stout, A. J., Arnett, M. J., Chai, K. M., Guo, T., Liao, L., Mirliani, A. B., Rittenberg, M. L., Shub, M., White, E. C., Yuen, J. S. K., Zhang, X., Kaplan, D. L. Abstract: For cultured meat to succeed at scale, muscle cells from food-relevant species must be expanded in vitro in a rapid and reliable manner to produce millions of metric tons of biomass annually. Toward this goal, genetically immortalized cells offer substantial benefits over primary cells, including rapid growth, escape from cellular senescence, and consistent starting cell populations for production. Here, we develop genetically immortalized bovine satellite cells (iBSCs) via constitutive expression of bovine Telomerase reverse transcriptase (TERT) and Cyclin-dependent kinase 4 (CDK4). These cells achieve over 120 doublings at the time of publication and maintain their capacity for myogenic differentiation. They therefore offer a valuable tool to the field, enabling further research and development to advance cultured meat. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Aging-US
USP7 Regulates Cyclin F Protein Stability

Aging-US

Play Episode Listen Later Nov 22, 2022 3:43


A new research paper was published in Aging (listed as “Aging (Albany NY)” by MEDLINE/PubMed and “Aging-US” by Web of Science) Volume 14, Issue 21, entitled, “The deubiquitylase USP7 is a novel cyclin F-interacting protein and regulates cyclin F protein stability.” Orderly progression through the cell cycle is driven by the periodic oscillations in the activity of cyclin-dependent kinases (CDKs). Cyclin F, unlike canonical and transcriptional cyclins, does not bind or activate any cyclin-dependent kinases. Instead, it harbors an F-box motif and primarily functions as the substrate recognition subunit of the Skp1-Cul1-F-box E3 ubiquitin ligase complex, SCFCyclin F. By targeting specific proteins for ubiquitin-mediated proteasomal degradation, cyclin F plays a critical role in the regulation of centrosomal duplication, DNA replication and repair, and maintenance of genomic stability. Cyclin F abundance and activity are tightly regulated throughout the cell cycle. However, the molecular mechanisms regulating cyclin F are scantily understood. In this new study, researchers Savitha S. Sharma, W. Jack Pledger and Paturu Kondaiah from Indian Institute of Science, Sri Shankara Cancer Hospital and Research Centre and University of Utah Health's Huntsman Cancer Institute identified the deubiquitylase USP7 as a novel cyclin F-interacting protein. “In this study, we identify USP7 as a novel cyclin F-interacting protein and uncover novel aspects of cyclin F regulation mediated by this interaction.” The team observed that USP7 stabilizes cyclin F protein and that this function is independent of the deubiquitylase activity of USP7. Additionally, their data suggest that USP7 is also involved in the regulation of cyclin F mRNA. Pharmacological inhibition of the deubiquitylase activity of USP7 resulted in downregulation of cyclin F mRNA. “In conclusion, in this study, we demonstrate a new interacting partner of cyclin F, namely USP7, and the role of USP7 in the regulation of cyclin F mRNA and protein. This study highlights a potential role for the cyclin F-USP7 axis in pathological conditions, including cancer and neurodegenerative diseases.” DOI: https://doi.org/10.18632/aging.204372 Corresponding Author: Savitha S. Sharma - savitha.sharma@ssnccpr.org Video: https://www.youtube.com/watch?v=NMGevJWU9Ac Keywords: cyclin F, atypical cyclins, USP7, cell cycle, genomic integrity About Aging-US: Launched in 2009, Aging (Aging-US) publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at www.Aging-US.com​​ and connect with us: SoundCloud – https://soundcloud.com/Aging-Us Facebook – https://www.facebook.com/AgingUS/ Twitter – https://twitter.com/AgingJrnl Instagram – https://www.instagram.com/agingjrnl/ YouTube – https://www.youtube.com/agingus​ LinkedIn – https://www.linkedin.com/company/aging/ Reddit – https://www.reddit.com/user/AgingUS Pinterest – https://www.pinterest.com/AgingUS/ For media inquiries, please contact media@impactjournals.com

Oncotarget
MK256 a Novel CDK8 Inhibitor With Antitumor Activity in AML Through Downregulation of STAT Pathway

Oncotarget

Play Episode Listen Later Nov 10, 2022 3:31


A new research paper was published in Oncotarget's Volume 13 on November 2, 2022, entitled, “MK256 is a novel CDK8 inhibitor with potent antitumor activity in AML through downregulation of the STAT pathway.” Acute myeloid leukemia (AML) is the most lethal form of AML due to disease relapse. Cyclin dependent kinase 8 (CDK8) is a serine/threonine kinase that belongs to the family of Cyclin-dependent kinases and is an emerging target for the treatment of AML. MK256, a potent, selective, and orally available CDK8 inhibitor was developed to target AML. In this new study, researchers Jen-Chieh Lee, Shu Liu, Yucheng Wang, You Liang, and David M. Jablons from the University of California San Francisco and Touro University sought to examine the anticancer effect of MK256 on AML. “In CD34+/CD38- leukemia stem cells, we found that MK256 induced differentiation and maturation.” Treatment of MK256 inhibited proliferation of AML cell lines. Further studies of the inhibitory effect suggested that MK256 not only downregulated phosphorylated STAT1(S727) and STAT5(S726), but also lowered mRNA expressions of MCL-1 and CCL2 in AML cell lines. Efficacy of MK256 was shown in MOLM-14 xenograft models, and the inhibitory effect on phosphorylated STAT1(S727) and STAT5(S726) with treatment of MK256 was observed in vivo. Pharmacologic dynamics study of MK256 in MOLM-14 xenograft models showed dose-dependent inhibition of the STAT pathway. Both in vitro and in vivo studies suggested that MK256 could effectively downregulate the STAT pathway. In vitro ADME, pharmacological kinetics, and toxicity of MK256 were profiled to evaluate the drug properties of MK256. “Our results show that MK256 is a novel CDK8 inhibitor with a desirable efficacy and safety profile and has great potential to be a promising drug candidate for AML through regulating the STAT pathway.” DOI: https://doi.org/10.18632/oncotarget.28305 Correspondence to: Jen-Chieh Lee -jenchieh.lee@ucsf.edu, Shu Liu - shu.liu@ucsf.edu Keywords: AML, CDK8, kinase inhibitor, STAT pathway, xenograft Video: https://www.youtube.com/watch?v=8bRgqTg9-c8 About Oncotarget: Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media: Twitter – https://twitter.com/Oncotarget Facebook – https://www.facebook.com/Oncotarget YouTube – www.youtube.com/c/OncotargetYouTube Instagram – https://www.instagram.com/oncotargetjrnl/ LinkedIn – https://www.linkedin.com/company/oncotarget/ Pinterest – https://www.pinterest.com/oncotarget/ LabTube – https://www.labtube.tv/channel/MTY5OA SoundCloud – https://soundcloud.com/oncotarget For media inquiries, please contact: media@impactjournals.com

Path for Potential
Episode 2 - Holly Tucker

Path for Potential

Play Episode Listen Later Aug 19, 2022 54:18


Mark and Johanna speak to 'Holly & Co' and 'notonthehighstreet' founder Holly Tucker in this episode. "Hurricane Holly" takes us through the early chapters of her career and what happens when you're a workaholic even from a very early age. We also cover the power that naivety can have and where it can take you, as well as the importance of doing what you love, or, loving what you do!

A Corporate Time with Tom and Dan
ACT - "Keep On Cyclin'" (Friday 8-5-22)

A Corporate Time with Tom and Dan

Play Episode Listen Later Aug 5, 2022 47:10


The far more censored version of the award-winning and unparalleled "A Mediocre Time with Tom and Dan." - "A Corporate Time" is a daily companion and terrestrial radio show heard nationally on iHeartRadio. It's silly.

cyclin mediocre time corporate time
BioTech IQ
#51 Cell Cycle Therapy: Understanding The Cell Cycle Biology To Treat Cancer With Spiro Rombotis

BioTech IQ

Play Episode Listen Later Jun 10, 2022 55:28


Cell cycle biology is key to understanding cancer. You have to hit the cancer cells early before they become smart and adapt. There is a stage in the cell cycle called mitosis. This is where, if done right, can cause cancer cells to suicide. This is where the biotech company, Cyclacel comes in with all their research into the cell cycle of cancer. Join Ammon Rivera as he talks to Spiro Rombotis about some of Cyclacel's cell cycle therapies. Spiro is the CEO of Cyclacel. His mission is to use cell cycle biology to treat cancer and other serious diseases. Ammon and Spiro go over the use of Cyclin-dependent Kinase and its role in the cell cycle. Spiro also talks about Cyclacel's pipeline and drug candidates. They also go through discussion strategy, the drug approval process, and what it means to fail fast.

Ewan for Breakfast - Triple M Limestone Coast 963
Ewan & Milo Talking Weekend Sports Results Footy Netball Soccer Cyclin and more

Ewan for Breakfast - Triple M Limestone Coast 963

Play Episode Listen Later May 23, 2022 12:42


See omnystudio.com/listener for privacy information.

My AP Biology Thoughts
Regulation of Cell Cycle

My AP Biology Thoughts

Play Episode Listen Later May 27, 2021 3:03


My AP Biology Thoughts  Unit 4 Cell Communication and Cell CycleWelcome to My AP Biology Thoughts podcast, my name is Alex Jing and I am your host for episode #96 called Unit 4 Cell Communication and Cell Cycle: Regulation of Cell Cycle. Today we will be discussing How cells regulate their division Segment 1: Introduction to Cell Cycle Regulation The cell cycle includes 4 main stages: G1, S, G2, and mitosis. These phases are responsible for the division of cells. However, how do the cells determine when they can proceed to the next stage of the cell cycle? Cells regulate their advancement in the cell cycle through the use of Cyclin-dependent kinases, or CDKs, and CDK inhibitors. When CDKs are active, they phosphorylate other enzymes in the cell responsible for activating the next stage of the cell cycle. CDK inhibitors are receptors that when activated, will inhibit the CDKs, preventing the cell from going to the next stage.  Segment 2: More About the Regulation of the Cell Cycle A prominent example of why CDKs and their inhibitors are so important is the development of cancer. Cancers form when cells are growing at an rapid, unrestricted rate, and are usually caused by some mutations in the cell which results in either overactive CDKs or inactive CDK inhibitors. P53 is a CDK inhibitor which is responsible for ensuring that DNA is not damaged during the replication process. If it detects damaged DNA it will send out signals to inhibit the CDKs. If a mutation caused the P53 to not be responsive, than cells could be able to divide with damaged DNA, leading to a new cancer to form. Segment 3: Connection to the Course Regulation of the cell cycle is an essential part of all living organisms. Being able to conduct mitosis is what allows organisms to grow and replace damaged cells, and being able to regulate this process is extremely important to ensuring that division is done correctly.  Thank you for listening to this episode of My AP Biology Thoughts. For more student-ran podcasts and digital content, make sure that you visit http://www.hvspn.com (www.hvspn.com).   Music Credits: "Ice Flow" Kevin MacLeod (incompetech.com) Licensed under Creative Commons: By Attribution 4.0 License http://creativecommons.org/licenses/by/4.0/ Subscribe to our Podcast https://podcasts.apple.com/us/podcast/my-ap-biology-thoughts/id1549942575 (Apple Podcasts) https://open.spotify.com/show/1nH8Ft9c9f6dmo75V9imCk (Spotify) https://podcasts.google.com/search/my%20ap%20biology%20thoughts (Google Podcasts )   https://www.youtube.com/channel/UC07e_nBHLyc_nyvjF6z-DVg (YouTube)  Connect with us on Social Media Twitterhttps://twitter.com/thehvspn ( @thehvspn)

My AP Biology Thoughts
CDK and Cyclins

My AP Biology Thoughts

Play Episode Listen Later May 25, 2021 5:19


My AP Biology Thoughts  Unit 4 Cell Communication and Cell CycleWelcome to My AP Biology Thoughts podcast, my name is Nidhi and I am your host for episode #95 called Unit 4 Cell Communication and Cell Cycle: CDK and Cyclins. Today we will be discussing what cyclins and CDK are and why they're important.  Segment 1: Introduction to CDK and CyclinsCyclins are a group of related proteins, and there are four basic types found in humans and most other eukaryotes. These include G1cyclins, G1/S cyclins, S cyclins, and M cyclins. Each cyclin is associated with a particular phase, transition, or set of phases in the cell cycle and helps drive the events of that phase or period. For instance, M cyclin promotes the events of the Mitosis phase, such as nuclear envelope breakdown and chromosome condensation. Cyclin-dependent kinases, or CDKs, are enzymes that catalyze the phosphorylation of target proteins in the cell cycle. The attached phosphate makes the target protein more or less active. The CDKs are activated when attached to cyclin because the cyclin changes the shape of the enzyme. When a cyclin attaches to a Cdk, it has two important effects: it activates the Cdk as a kinase, but it also directs the Cdk to a specific set of target proteins ensuring that those are proteins appropriate to the cell cycle period controlled by the cyclin. After the phosphorylation of proteins is complete, cyclin breaks down and CDK is inactive. CDK-Cyclins also act as a control or regulator for the cell cycle. Cdk activity and target proteins change as levels of the various cyclins rise and fall. In addition to needing a cyclin, Cdks must also be phosphorylated on a particular site in order to be active. Segment 2: More About CDK and Cyclins An example of how cyclins and cdks work is the mitosis-promoting factor. A MPF molecule is a CDK bound to an M cyclin. As the cell approaches the G2/ Mitosis transition phase in the cycle, the levels of the M cyclin increase. It then binds to CDKs present in the cell and together they cause the Mitosis phase to begin. The MDF adds phosphate to protein in the nuclear envelope, causing it to break down, and activates chromosome condensation promoting targets. In addition to driving the events of M phase, MPF also triggers its own destruction by activating the anaphase-promoting complex/cyclosome or APC/C, a protein complex that causes M cyclins to be destroyed starting in anaphase. The destruction of M cyclins pushes the cell out of mitosis, allowing the new daughter cells to enter G1.  CDKs and cyclins often respond to cues from the cell to regulate. Positive cues, like growth factors, increase activity of Cdks and cyclins, while negative ones, like DNA damage, usually decrease activity. When DNA damage occurs, a protein called p53 triggers the production of CDK inhibitor proteins. These proteins bind to Cdk-cyclin complexes and block their activity, allowing time for DNA repair to occur. By ensuring that cells don't divide when their DNA is damaged, mutations are not being passed onto daughter cells. When p53 is defective or missing, mutations can accumulate, potentially leading to cancer  Segment 3: Connection to the Course Cylins and CDK can connect to the principles of evolution. Cyclins and Cdks are found in many different types of species, from yeast to frogs to humans. They vary slightly in each organism. For example, yeast has just one Cdk, while humans and other mammals have multiple Cdks that are used at different stages of the cell cycle. These common enzymes and proteins can provide evidence of a common ancestor between these species.  Thank you for listening to this episode of My AP Biology Thoughts. For more student-ran podcasts and digital content, make sure that you visit http://www.hvspn.com (www.hvspn.com)!  Music Credits: "Ice Flow" Kevin MacLeod (incompetech.com) Licensed under Creative Commons: By Attribution 4.0 License...

Soft Talk
Sezonul 1, Episodul 5 - Soft Talk cu Teodora Nemeș

Soft Talk

Play Episode Listen Later Apr 25, 2021 38:59


Invitata zilei de 20 aprilie 2021 a fost Teodora Nemeș, elevă în clasa a XI-a la Liceul de Informatică “Tiberiu Popoviciu" din Cluj-Napoca. Teodora ne-a inspirat prin voluntariatele sale şi implicarea în numeroase proiecte, dintre care Cyclin.go este deja un succes. Vă invităm să aflați cum acest proiect a fost finanțat la Imperiul Leilor şi ce șanse are în cadrul acceleratorului Innovation Labs, de a caştiga încă o finanțare.

PaperPlayer biorxiv biochemistry
Discriminative SKP2 interactions with CDK-cyclin complexes support a cyclin A-specific role in p27KIP1 degradation

PaperPlayer biorxiv biochemistry

Play Episode Listen Later Oct 8, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.08.329599v1?rss=1 Authors: Salamina, M., Montefiore, B. C., Liu, M., Wood, D. J., Heath, R., Ault, J. R., Wang, L.-Z., Korolchuk, S., Basle, A., Pastok, M. W., Reeks, J., Tatum, N. J., Sobott, F., Arold, S. T., Pagano, M., Noble, M. E. M., Endicott, J. A. Abstract: The SCFSKP2 ubiquitin ligase relieves G1 checkpoint control of CDK-cyclin complexes by promoting p27KIP1 degradation. We describe reconstitution of stable complexes containing SKP1-SKP2 and CDK1-cyclin B or CDK2-cyclin A/E, mediated by the CDK regulatory subunit CKS1. We further show that a direct interaction between a SKP2 N-terminal motif and cyclin A can stabilize SKP1-SKP2-CDK2-cyclin A complexes in the absence of CKS1. We identify the SKP2 binding site on cyclin A and demonstrate the site is not present in cyclin B or cyclin E. This site is distinct from but overlapping with features that mediate binding of p27KIP1 and other G1 cyclin regulators to cyclin A. We propose that the capacity of SKP2 to engage with CDK2-cyclin A by more than one structural mechanism provides a way to fine tune the degradation of p27KIP1 and distinguishes cyclin A from other G1 cyclins to ensure orderly cell cycle progression. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv biochemistry
Structural basis for the activation of CDK7 by MAT1 and Cyclin H

PaperPlayer biorxiv biochemistry

Play Episode Listen Later Aug 21, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.20.258632v1?rss=1 Authors: Peissert, S., Schlosser, A., Kendel, R., Kuper, J., Kisker, C. Abstract: CDK7, Cyclin H, and MAT1 form the heterotrimeric CDK activating kinase (CAK) complex. CAK is a vital factor for the two essential processes of transcription and cell cycle control. When associated with the general transcription factor II H (TFIIH) it activates RNA polymerase II by hyperphosphorylation of its C-terminal domain (CTD). In the absence of TFIIH it phosphorylates the T-loop of CDKs that control cell cycle progression. CAK holds a special position among the CDK branch due to this dual activity and the dependence on the MAT1 protein for activation in addition to Cyclin H. We solved the structure of the CAK complex from the model organism C. thermophilum at 2.6 [A] resolution. Our structure reveals an intricate network of interactions between MAT1 and its two binding partners CDK7 and Cyclin H providing a structural basis for the mechanism of CDK7 activation and CAK activity regulation. In vitro activity measurements combined with functional mutagenesis show that CDK7 activation can occur independently of T-loop phosphorylation and is thus exclusively MAT1 dependent by positioning the CDK7 T-loop in its active conformation. Finally, our structure of the active CAK with a peptide model provides a molecular rationale for heptad repeat phosphorylation. Copy rights belong to original authors. Visit the link for more info

Carolina Outdoors
Cyclin’ Around Town

Carolina Outdoors

Play Episode Listen Later Jul 29, 2020 18:59


(From The 07/18/2020 Show) Joining into the Carolina Outdoors show today is Jesse Browns’ own Tom Pearman chatting about biking in and around the Carolinas. Whether you’re new to the sport or a regular bike jockey, you will be in for a treat learning about the preparation for a trip, why drinking plenty of water is important, and how to stay safe with proper cycling etiquette wherever you ride.

Les interviews d'Inter
Éléonore Gaspa, cofondatrice de Cyclin’Jaipur en Inde

Les interviews d'Inter

Play Episode Listen Later May 27, 2020 4:45


durée : 00:04:45 - Déjà debout - par : Mathilde MUNOS - Éléonore Gaspa, cofondatrice de Cyclin’Jaipur et fondatrice de Carnet de Voyages en Inde.

Déjà debout
Éléonore Gaspa, cofondatrice de Cyclin’Jaipur en Inde

Déjà debout

Play Episode Listen Later May 27, 2020 4:45


durée : 00:04:45 - Déjà debout - par : Mathilde MUNOS - Éléonore Gaspa, cofondatrice de Cyclin’Jaipur et fondatrice de Carnet de Voyages en Inde.

Le 5/7
Éléonore Gaspa, cofondatrice de Cyclin’Jaipur en Inde

Le 5/7

Play Episode Listen Later May 27, 2020 4:45


durée : 00:04:45 - Déjà debout - par : Mathilde MUNOS - Éléonore Gaspa, cofondatrice de Cyclin’Jaipur et fondatrice de Carnet de Voyages en Inde.

Spermula
Cyclin’ Through

Spermula

Play Episode Listen Later May 20, 2020 21:06


We talk all the tracking ish, trials, tribulations and what we’re up to know in these times!

CME Outfitters, LLC Podcasts
Real-World Evidence: Cyclin-Dependent Kinase 4/6 Inhibitors in Hormone Receptor-Positive Metastatic Breast Cancer

CME Outfitters, LLC Podcasts

Play Episode Listen Later May 15, 2020 43:33


PaperPlayer biorxiv neuroscience
A cyclin-dependent kinase 5-derived peptide inhibits Cdk5p25 activity and improves neurodegenerative phenotypes

PaperPlayer biorxiv neuroscience

Play Episode Listen Later May 14, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.12.090472v1?rss=1 Authors: Seo, J., Pao, P.-C., Kritskiy, O., Lee, A., Patnaik, D., Watson, L. A., Bula, M., Barker, S. J., Penney, J., Silva, M. C., Haggarty, S. J., Tsai, L.-H. Abstract: Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This effect is mediated by pathological cleavage of the Cdk5 activator p35 to produce the truncated product p25, exhibiting increased stability and altered substrate specificity. The benefit of blocking p25 production has been demonstrated in various rodent and human neurodegenerative models. However, important Cdk5/p35 functions in the developing and adult brain have made it challenging to selectively target the detrimental effects of Cdk5/p25 while sparing the physiological functions of Cdk5/p35. Here, we report a 12-amino acid-long peptide fragment derived from Cdk5 (the Cdk5 inhibitory (Cdk5i) peptide) that shows a high binding affinity toward the Cdk5/p25 complex and can efficiently and selectively inhibit Cdk5/p25 kinase activity. Using cellular assays, mouse neurodegeneration models and human cerebral organoids generated from patient-derived iPSCs, we demonstrate beneficial effects of the Cdk5i peptide on various pathological phenotypes including gliosis, DNA damage, and Tau hyperphosphorylation. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv neuroscience
Probing the functions of microglial cyclin-dependent kinase 5 under physiological and pathological conditions

PaperPlayer biorxiv neuroscience

Play Episode Listen Later May 14, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.12.090605v1?rss=1 Authors: Peng, Z., Huang, W.-C., Chen, M., Penney, J., Cam, H., Abdurrob, F., Akay, L., Chen, X., Ralvenius, W., Rubino, L. P., Tsai, L.-H. Abstract: Cyclin dependent kinase 5 (Cdk5) regulates various developmental and physiological processes in the central nervous system. Deregulation of Cdk5 activity in neurons induces severe neurodegeneration and has been implicated in Alzheimers disease (AD) and other neurodegenerative conditions. A large fraction of AD risk genes are highly expressed in microglia, highlighting an important role for these cells in AD pathogenesis. While Cdk5 function in neurons is well characterized, our understanding of its roles in microglial function under physiological and neurodegenerative conditions remain rudimentary. Here, we investigate the roles of Cdk5 in microglia using myeloid-specific Cdk5 conditional knockout mice. Using microglia-specific transcriptome profiling, histological analyses, and behavioral assessments, we found that knockout of Cdk5 in microglia for 1 month induced transcriptional changes characterized by upregulation of cell cycle processes and type I interferon signaling genes in both physiological conditions and AD-related amyloidogenesis. In contrast to the robust transcriptional changes, conditional loss of microglial Cdk5 produced minimal effects on the density and morphology of microglia and their phagocytic activity toward myelin debris. Moreover, Cdk5cKO mice exhibited little change in synaptic density and tasks associated with locomotor, anxiety-like, and memory-related behaviors. Our findings indicate that the conditional loss of Cdk5 in microglia induces rapid alterations of microglial transcriptome with minimal or delayed effects on histological and behavioral responses. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv neuroscience
BioID analysis of the cyclin F interactome reveals that ALS-variant cyclin F alters the homeostasis of paraspeckle-associated proteins

PaperPlayer biorxiv neuroscience

Play Episode Listen Later May 1, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.30.071365v1?rss=1 Authors: Rayner, S. L., Cheng, F., Yang, S., Grima, N., Ke, Y. D., Au, C. G., Morsch, M., De Luca, A., Davidson, J. M., Molloy, M. P., Shi, B., Ittner, L. M., Blair, I., Chung, R. S., Lee, A. Abstract: Background: Previously, we identified missense mutations in CCNF that are causative of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). CCNF encodes for the protein cyclin F, a substrate recognition component of the E3-ubiquitin ligase, SCFcyclin F. We have previously shown that mutations in CCNF cause disruptions to overall protein homeostasis; causing a build-up of ubiquitylated proteins (1) as well as defects in autophagic machinery (2). Methods: Here, we have used an unbiased proteomic screening workflow using BioID, as well as standard immunoprecipitations to identify novel interaction partners of cyclin F, identifying the interaction between cyclin F and a series of paraspeckle proteins. The homeostasis of these new cyclin F interaction partners, RBM14, NONO and SFPQ were monitored in primary neurons using immunoblotting. In addition, the homeostasis of RBM14 was compared between control and ALS/FTD patient tissue using standard IHC studies. Results: Using BioID, we found over 100 putative interaction partners of cyclin F and demonstrated that cyclin F closely associates with a number of essential paraspeckle proteins, which are stress-responsive proteins that have recently been implicated in ALS pathogenesis. We further demonstrate that the turnover of these novel binding partners are defective when cyclin F carries an ALS/FTD-causing mutation. In addition the analysis of RBM14 levels in ALS patient post-mortem tissue revealed that RBM14 levels were significantly reduced in post-mortem ALS patient motor cortex and significantly reduced in the neurons of spinal cord tissue. Conclusion: Overall, our data demonstrate that the dysregulation of paraspeckle components may be contributing factors to the molecular pathogenesis of ALS/FTD. Copy rights belong to original authors. Visit the link for more info

The TriDot Podcast
How to Remove 8 Common Barriers to Swim Improvement

The TriDot Podcast

Play Episode Listen Later Nov 21, 2019 50:00


In this episode, our two expert coaches will explain eight common barriers preventing triathletes from improving in their swim and how to remove them. We warm up sharing some of our own embarrassing triathlon moments, dive into our swim discussion for the main set, and then cool down with a Race Recon from Ironman Louisville.

Blood & Cancer
Breast Cancer, CDK4/6 Inhibitors

Blood & Cancer

Play Episode Listen Later Apr 4, 2019 30:03


We'd love to hear from you with ideas, suggestions, feedback, and questions for Dr. Henry or Dr. Yurkeiwicz at podcasts@mdedge.com and you can follow MDedge Hematology/Oncology at @MDedgeHemOnc.   Blood & Cancer episode 10:CDK4/6 inhibitors in breast cancer Richard Finn, MD, of the Geffen School of Medicine at UCLA joins guest host Jame Abraham, MD, of the Cleveland Clinic to discuss CDK4/6 inhibitors in the treatment of breast cancer, from the first pivotal studies to efficacy and patient selection. Later, Ilana Yurkiewicz, MD, talks about why it’s problematic to tell patients there is no more treatment in this week’s Clinical Correlation. Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford University and is also a columnist for Hematology News.   Show notes By Emily Bryer, DO, Resident in the department of internal medicine, University of Pennsylvania. Cyclin dependent kinase 4 and 6 (CDK4/6) control phosphorylation of the retinoblastoma gene product in the G1 to S transition of the cell cycle. Luminal ER-positive HER2-negative breast cancers are most sensitive to inhibition with a CDK4/6 inhibitor and act synergistically with tamoxifen. PALOMA 1 trial studied CDK4/6 Inhibitors in ER-positive breast cancer. Letrozole alone (10-month PFS) versus letrozole plus palbociclib (greater than 20-month PFS) Toxicity = grade 3 (ANC 500-1000) and grade 4 neutropenia (ANC less than 500) Low incidence of neutropenic fever Palbociclib and chemotherapy have distinct effects on the bone marrow. Palbociclib is cytostatic (also, toxicity is predictable and not cumulative) Chemotherapy is cytocidal Although efficacy is similar between CDK4/6 inhibitors (PFS hazard ratio +/-0.5), side effects vary. Ribociclib and palbociclib have a higher incidence of neutropenia Ribociclib affects QTC interval and liver enzymes Abemaciclib is associated with diarrhea and venous thromboembolism Ongoing studies are exploring 1) CDK4/6 inhibitor plus endocrine therapy versus endocrine therapy alone and 2) CDK4/6 inhibitors in the adjuvant setting. The population to most benefit from CDK4/6 inhibitors may include the patients who are high-risk for relapse following endocrine therapy alone (previously those who would also receive chemotherapy). Additional reading N Engl J Med 2018; 379:1926-36. Breast Cancer. 2018 Jul;25(4):402-6.

Oncotarget
ERβ inhibits cyclin dependent kinases 1 and 7 in triple negative breast cancer

Oncotarget

Play Episode Listen Later Nov 15, 2017 42:51


Full text - http://bit.ly/2mlYU6k "ERβ inhibits cyclin dependent kinases 1 and 7 in triple negative breast cancer" Abstract - Triple negative breast cancer (TNBC), which comprises approximately 15% of all primary breast cancer diagnoses, lacks estrogen receptor alpha, progesterone receptor and human epidermal growth factor receptor 2 expression. However, we, and others, have demonstrated that approximately 30% of TNBCs express estrogen receptor beta (ERβ), a nuclear hormone receptor and potential drug target. Treatment of ERβ expressing MDA-MB-231 cells with estrogen or the ERβ selective agonist, LY500307, was shown to result in suppression of cell proliferation. This inhibitory effect was due to blockade of cell cycle progression. In vivo, estrogen treatment significantly repressed the growth of ERβ expressing MDA-MB-231 cell line xenografts. Gene expression studies and ingenuity pathway analysis identified a network of ERβ down-regulated genes involved in cell cycle progression including CDK1, cyclin B and cyclin H. siRNA mediated knockdown or drug inhibition of CDK1 and CDK7 in TNBC cells resulted in substantial decreases in proliferation regardless of ERβ expression. These data suggest that the tumor suppressive effects of ERβ in TNBC result from inhibition of cell cycle progression, effects that are in part mediated by suppression of CDK1/7. Furthermore, these data indicate that blockade of CDK1/7 activity in TNBC may be of therapeutic benefit, an area of study that has yet to be explored. Facebook - http://bit.ly/2xznxjV Twitter - http://bit.ly/2xzWvsu LinkedIn - http://bit.ly/2xzJ6kc Pintrest - http://bit.ly/2xzX8SS Reddit - http://bit.ly/2hoxI0N www.Oncotarget.com

Oncotarget
Dr. Hawse - ERβ inhibits cyclin dependent kinases 1 and 7 in triple...

Oncotarget

Play Episode Listen Later Nov 13, 2017 7:23


Full text - bit.ly/2mlYU6k Interview with Dr. John R. Hawse from the Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA talking about their paper "ERβ inhibits cyclin dependent kinases 1 and 7 in triple negative breast cancer" Facebook - http://bit.ly/2xznxjV Twitter - http://bit.ly/2xzWvsu LinkedIn - http://bit.ly/2xzJ6kc Pintrest - http://bit.ly/2xzX8SS Reddit - http://bit.ly/2hoxI0N www.Oncotarget.com

St Gallen 2017
Cyclin dependent kinases to treat metastatic breast cancer

St Gallen 2017

Play Episode Listen Later Aug 1, 2017 2:56


Dr Loibl speaks with ecancer at the 2017 St. Gallen International Breast Cancer Conference about ongoing trials of CDK 4/6 inhibitors to treat metastatic breast cancer.

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 05/06
Cyclin-dependent kinase 5 stabilizes the hypoxia-inducible factor in hepatocellular carcinoma

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 05/06

Play Episode Listen Later Jan 28, 2015


Wed, 28 Jan 2015 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/18655/ https://edoc.ub.uni-muenchen.de/18655/1/Herzog_Julia.pdf Herzog, Julia ddc:540, ddc:500, Fakultät fü

LectureBank
CellBio 11.11.14 Kriwacki Cyclin and Even More Kinases

LectureBank

Play Episode Listen Later Nov 25, 2014


Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 05/06
Targeting cyclin dependent kinase 5 in hepatocellular carcinoma

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 05/06

Play Episode Listen Later Jul 25, 2014


For a long time cyclin dependent kinase 5 (Cdk5) was thought to be of exclusive importance in neuronal cells. However, recently increasing evidence suggests a function of Cdk5 in cancer progression. In the present study, we examined the role of Cdk5 in hepatocellular carcinoma (HCC), a highly chemoresistant cancer with poor prognosis. Consequently, development of novel targeted therapies for HCC is of paramount clinical importance. Analysis of human HCC patient samples showed an increased expression of Cdk5 as compared to normal liver tissues. Functional ablation of Cdk5 significantly decreases HCC cell proliferation and clonogenic survival, and reduces cell motility and invasion. Of note, genetic as well as pharmacologic inhibition of Cdk5 also shows in vivo efficacy in a HCC xenograft mouse model. Investigating the mechanism behind these functional effects revealed that Cdk5 is most active in the nucleus of cells in G2/M phase. In this cell cycle phase DNA damage response takes place, which is affected by Cdk5 inhibition. Furthermore, Cdk5 leads to phosphorylation of Ataxia Telangiectasia Mutated (ATM) and thereby influence its downstream signaling. Importantly, combination of Cdk5 inhibition with different DNA damage inducing chemotherapeutics or the first-line systemic drug sorafenib inhibits synergistically HCC tumor progression. In conclusion, we introduce: 1. Cdk5 as a novel drugable target for treatment of HCC 2. The combination of Cdk5 inhibition and DNA damage agents as a novel therapeutic approach 3. An increased efficacy of sorafenib treatment by combing with Cdk5 inhibition

Frontiers in Cardiac and Vascular Regeneration
G. Matrone - Role of Cyclin-Dependent Kinase-9 in cardiac injury-recovery in the zebrafish embryo

Frontiers in Cardiac and Vascular Regeneration

Play Episode Listen Later Jun 1, 2012 13:24


Guido Matrone Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh - UK, speaks on "Role of Cyclin-Dependent Kinase-9 in cardiac injury-recovery in the zebrafish embryo" . This seminar has been recorded by ICGEB

4th IMPAKT Breast Cancer Conference
New cyclin-dependent kinase inhibitor with letrozole for ER+/HER2- breast cancer: Prof Richard Finn - Universtity of California

4th IMPAKT Breast Cancer Conference

Play Episode Listen Later May 29, 2012 7:56


Prof Finn talks to ecancer at at the IMProving care And Knowledge through Translational research (IMPAKT) meeting in Brussels, May 2012, about the results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for firstline treatment of ER+/HER2- advanced breast cancer. The new compound has the potential to be a standard of care in this setting, if a phase 3 study is successful, and also has promise in the adjuvant setting.

Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 14/19
Molekular gezielte Therapie des Mantelzelllymphoms - In Vitro Wirksamkeit von Flavopiridol in Mono- und Kombinationstherapie

Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 14/19

Play Episode Listen Later Mar 1, 2012


Das Mantelzelllyphom wird analog zu den indolenten NHL als nicht kurabel eingestuft, weist jedoch ein signifikant verkürztes medianes Gesamtüberleben auf und stellt somit für die Klinik eine Kombination aus den negativen Eigenschaften von indolenten und aggressiven Lymphomen dar. Das MCL stellt trotz intensiver Therapie aufgrund seiner frühzeitigen Rezidive eine große Herausforderung an die Medizin. Eine große Anzahl neuer Substanzen werden z.Z. auf ihre Wirksamkeit beim MCL geprüft. Zwei dieser Stoffe sind Flavopiridol, ein molekularer Serin/Threonin-Kinase-Inhibitor, und Bendamustin, ein bereits in der Klinik etabliertes Zytostatikum. Gegenstand dieser Arbeit ist zum einen die bessere Charakterisierung der Wirkung beider Substanzen auf MCL-Zelllinien in vitro, sowohl als Monotherapie als auch in Kombination mit anderen Medikamenten. Hauptziel ist es, einen potentiellen Synergismus der untersuchten Medikamente aufzudecken und den genaueren Effekt auf die Tumorzellen zu charakterisieren. Die in vitro Untersuchungen der vorliegenden Arbeit weisen eine dosis- und zeitabhängige zytotoxische Aktivität von Bendamustin nach, und spiegeln somit die hohe klinische Effektivität bei der Behandlung des MCL wieder. Ebenso konnte anhand der hier gezeigten Versuchsreihen demonstriert werden,dass der Cyclin-abhängige-Kinasen-Inhibitor Flavopiridol als Monosubstanz hochwirksam gegen MCL-Zelllinien in vitro ist. Nach Behandlung mit Flavopiridol konnte in allen untersuchten Zelllinien in klinisch realisierbaren Dosierungen Apoptose induziert werden, Verringerungen der CDK-Expression nachgewiesen, und darüber hinaus eine potente Inhibition des Zellzyklus im Sinne eines G1/S und G2/M Arrest demonstriert werden. Die selektive Hemmung der CDKs stellt somit einen attraktiven, zielgerichteten Ansatz in der Tumortherapie dar, denn diese Enzyme sind in den meisten malignen Zellen zur Aufrechthaltung einer unbegrenzten Proliferation notwendig. Für die Kombination von Flavopiridol mit Enzastaurin und Rad001 konnte, ins besonders in resistenten Zellreihen, ein mehr als additiver Effekt gezeigt werden; diese Erkenntnis spricht für eine Komplementarität in der antineoplastischen Wirkung dieser Substanzen bei zeitgleicher Inhibition der jeweiligen zellulären Zielstrukturen. Andererseits konnte für Kombinationen von Flavopiridol mit antimetabolischwirkenden Chemotherapeutika und Bendamustin, bei gleichzeitiger Anwendung, nur antagonistische Effekte beobachtet werden. Hier scheint der durch Flavopiridol verursachte potente Zyklusarrest am G1/SÜbergang der Grund für die verminderte Wirksamkeit der verwendeten phasenspezifischen Medikamente zu sein. Diese Resultate untersteichen die enorme Bedeutung der Sequenz bei der Verabreichung von zytostatisch wirkenden Stoffen in der Therapie von Malignomen. Die Erkenntnisse über edikamentenwirkungen aus in vitro Experimenten lassen sich allerdings nicht ohne weiteres auf komplexe Systeme in vivo übertragen und müssen deshalb berücksichtigt werden. Folgende Gründe sind hierfür ursächlich: Zum einen sind viele wichtige antineoplastische Mechanismen in der Zellkultur nicht messbar bzw. quantifizierbar, etwa eine Hemmung der Angioneogenese, Veränderungen des Mikromilieus der Tumorzellen oder zelluläre Immunantworten. Zum anderen sind die Biodistribution, die Pharmakodynamik und die Pharmakokinetik in vivo entscheidend, ob überhaupt eine Wirkung des Medikaments an der Tumorzelle entfaltet werden kann. Die Auswirkungen dieser Faktoren in komplexen biologische Systemen sind jedoch in vitro nicht einwandfrei zu beurteilen und können, am Beispiel von Flavopiridol, zu falschen Rückschlüssen bei der klinischen Anwendung eines Medikaments führen.

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 04/06
Cyclin-dependent kinase 5 in endothelial cell migration: Elucidating regulatory mechanisms upstream of Cdk5 and evaluating novel Cdk inhibitors as anti-angiogenic drugs

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 04/06

Play Episode Listen Later Oct 25, 2011


Tue, 25 Oct 2011 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/13648/ https://edoc.ub.uni-muenchen.de/13648/1/Weitensteiner_Sabine.pdf Weitensteiner, Sabine

Cancer Newsline - 2010
Low forms of Cyclin E reduces drug's effectiveness - February 9, 2010

Cancer Newsline - 2010

Play Episode Listen Later Feb 9, 2010 6:49


Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 10/19
Role of 3’UTR Elements in the Regulation of the Cyclin D1 Proto-oncogene

Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 10/19

Play Episode Listen Later Jul 15, 2009


Deregulation of the cell cycle regulator cyclin D1 in a wide variety of tumors has highlighted the role of cell cycle alterations in cancer. Genomic amplifications, mutations or balanced chromosomal translocations involving this gene are believed to lead to its aberrant overexpression in tumors. Somatic mutations in the 3’UTR of cyclin D1 gene have been reported in breast cancer, neuroblastoma and mantle cell lymphoma patients although their contribution to the cyclin D1 deregulation is unclear. In our study, we confirmed a regulatory role of the 3’UTR in cyclin D1 expression. Our results demonstrated that deletion of the cyclin D1 3’UTR significantly alters cyclin D1 protein expression and function. Similarly, the introduction of mutations observed in MCL patients in the cyclin D1 3’UTR significantly increased the expression of the cyclin D1 protein. These results underline that in malignancies such as MCL, truncation of the 3’UTR due to genomic deletions or somatic mutations is a likely cause of cyclin D1 overexpression. In order to ascertain whether the deletion of the cyclin D1 3’UTR could impart proliferative properties to cells, thereby contributing to transformation, we assessed the phenotype of fibroblasts retrovirally transduced with cyclin D1 with or without the 3’UTR. Interestingly our results demonstrated marked changes in cyclin D1 function upon deletion of the cyclin D1 3’UTR. Cells expressing cyclin D1 without the 3’UTR proliferated significantly more than those expressing the full length cyclin D1. Similar results were observed in rat ileum epithelial cells which lack the endogenous cyclin D1. Thus our data confirm that the deletion of the 3’UTR confers a proliferative advantage to cells. Furthermore, in this dissertation, we focused on the different potential regulatory elements of the cyclin D1 3’UTR to assess their role in controlling cyclin D1 expression. We reasoned that elements in the 3’UTR that are responsible for the controlled expression of the cyclin D1 protein are lost in 3’UTR deleted tumors. Therefore, it would be interesting to specifically pinpoint the role of these elements and highlight their contribution to cyclin D1 protein expression. It is assumed that since AU-rich elements (AREs) in the 3’UTR of cyclin D1 could have a potential destabilizing effect on the cyclin D1 mRNA, their loss could contribute to the observed overexpression of cyclin D1. Importantly, using highly sensitive reporter assays, we showed that the targeted loss of AREs from an otherwise intact 3’UTR leads to a decrease in reporter expression. These results demonstrate that the loss of these cis-acting elements in 3’UTR deleted tumors cannot account for cyclin D1 overexpression and there must be additional factors involved. Using bioinformatic analysis, we identified putative binding sites for microRNAs, small regulatory non-coding RNAs that have been shown to have important roles in cancer. Our study confirmed that microRNAs of the miR-15/16 family and the miR-17-92 cluster directly target the cyclin D1 gene through post-transcriptional regulation. These microRNAs have been shown to be involved in a cell cycle regulation and in a number of malignancies, especially in B-cell lymphoma. The various forms of cyclin D1 generated by deletions or mutations in the 3”UTR of cyclin D1 in tumors exclude these microRNA binding sites. Taken together, our results demonstrate a regulatory role for the 3’UTR in cyclin D1 expression and function. We show that the deletion of the cyclin D1 3’UTR leads to cyclin D1 overexpression and confers a proliferative advantage to cells. Finally, our results characterize the regulators functions of the different cis and trans-acting elements of the cyclin D1 3’UTR and identify this region as a bona fide target of cell cycle regulatory microRNAs. Extending these findings to other oncogenes, it is conceivable that the escape of 3’UTR mediated regulation by the acquisition of additional mutations of this region is an under-appreciated mechanism in the pathogenesis of cancer.

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 03/06
Characterization of the Cyclin Dependent Kinase Complex Bur1-2 and its Interaction with RPA

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 03/06

Play Episode Listen Later Dec 18, 2008


Gene expression is highly regulated and interconnected to processes like mRNP processing, mRNA export as well as to DNA repair and replication. The first step of gene expression is the transcription of protein coding genes by RNA polymerase II. Transcription is controlled by general transcription factors, the phosphorylation of the C-terminal domain of Rpb1, the largest subunit of RNA polymerase II, and chromatin modifications that allow proper accessibility of the DNA. A major player in these coupling processes is the TREX complex, coupling transcription elongation to the nucleo-cytoplasmic export of the mRNP via the nuclear pore complex. Particularly, the THO subcomplex of TREX has functions in hyperrecombination, nucleotide excision repair and transcription coupled repair. A genetic screen with TREX components, performed to identify genes involved in these processes, lead to the identification of the cyclin dependent kinase Bur1. Bur1 and its cyclin Bur2 are needed for efficient transcription elongation by RNA polymerase II by regulating the methylation of histone tails. Interestingly, Bur1 interacts in vivo with RPA, a single strand DNA binding protein essential for genome stability. This biochemical interaction raised the idea of a novel interconnection between transcription, chromatin modification and genome maintenance. Mutations in the BUR1 as well as in the RFA1 gene lead to sensitivity to drugs that cause DNA damage and replication or transcription stress. Deletion of the C-terminus of Bur1, which is sufficient for the binding to RPA, also renders cells sensitive to those agents. This shows the functional significance of this protein-protein interaction in the cell upon stress induction. However, attempts to identify the DNA repair pathway Bur1 is involved in showed that mutations in BUR1 do not behave epistatic with deletions of specific pathways. This result points to a more general, maybe regulatory role of Bur1 in the response to DNA damage. It is interesting to note that mutations in BUR1 lead to increased genomic instability as they show the appearance of a higher amount and longer persistence of nuclear foci, DNA repair “factories” that contain, among other proteins, Rfa1 and Rad52. Furthermore, RFA1 mutants show decreased levels of histone H3 alone as well as lower levels of histone H3 Lysine 4 trimethylation, a mark for transcription elongation, when combined with a mutation in BUR1. The RFA1 mutant is also impaired in the expression of a β-galactosidase reporter gene, pointing to a function of RPA in transcription. Interestingly, combining BUR1 and RFA1 mutants leads to a lower susceptibility of cells to stress than one of the mutations alone. On the one hand, this could be elucidated by better growth of the double mutant strains upon stress compared to the single mutants. On the other hand, whole genome expression analysis shows that the double mutant strain clusters with the bur1 mutant whereas the rfa1 mutant does not, showing that its expression pattern is closer to the bur1 mutant. Both results show that the protein complexes have antagonistic roles as the combination of both mutations leads to a suppression phenotype based on differential gene expression. Taken together, a function of Bur1 in genome maintenance could be established, as well as an effect of RPA on transcription elongation and chromatin modification. The results provide a possibility to speculate about a coupling of transcription and genome stability mediated by the interaction of Bur1-2 with RPA.

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 03/06
Anti-angiogenic effects of Cyclin dependent kinase inhibitors

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 03/06

Play Episode Listen Later Nov 21, 2008


Fri, 21 Nov 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/12402/ https://edoc.ub.uni-muenchen.de/12402/1/Liebl_Johanna.pdf Liebl, Johanna ddc:540, ddc:500, Fakultät für Chemie und Pharmazie

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06
Exploring the regulation and function of human Lats1 and Aurora A kinases in mitosis

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06

Play Episode Listen Later Aug 30, 2007


Mitosis is the process by which sister chromatids are equally segregated into two daughter cells. Tight control in various events during mitotic progression is essential for maintaining chromosome stability. Mitotic kinases including Cyclin dependent kinase 1 (Cdk1) and Aurora family are required for regulating proper mitotic progression by phosphorylating mitotic substrates thereby, controlling their activities, localization or abundance. On the other hand, these mitotic kinases are modulated by de-novo synthesis, activators, phosphorylation and ubiquitin-dependent proteolysis. A thorough understanding of the function and regulation of mitotic kinases could further our knowledge on mitotic progression. In the first part of the thesis, we investigated the expression, localization and regulation of human Lats1 kinase, which is a close homologue of the yeast Dbf2 kinase family involved in the mitotic exit network (MEN). Despite the fact that Lats1 has been suggested to be a spindle protein that binds and inactivates Cdk1, we found that Lats1 is mainly cytoplasmic throughout the cell cycle by immunofluorescence microscopy. Both yeast two-hybrid and coimmunoprecipitation showed no significant interaction between Lats1 and Cdk1. Although Lats1 was highly phosphorylated during mitosis, no detectable kinase activity was observed. However, we identified Ste20 like kinase MST2 as the upstream regulator of human Lats1. Phosphorylation of Lats1 by Mst2 resulted in the activation of Lats1 kinase activity both in vivo and in vitro. This kinase-substrate relation was proven to be specific, as another distant Mst2 homolog, Mst4, did not possess this ability. Subsequent mass-spectrometry-based phosphosites analysis revealed that Mst2 phosphorylates Lats1 on more than five residues. Alanine mutations on Lats1T1079 and S909 impaired Lats1 kinase activity. Thus, we could not confirm the suggested role of Lat1 in mitosis. Instead, we show that similar to its Drosophila ortholog, Lats1 is involved in the Mst2 signaling pathway and might control developmentally regulated cell proliferation and apoptosis in mammals. In the second part of this thesis, we characterized hBora, a novel Aurora A interactor originally found in Drosophila. We show that hBora is upregulated and phosphorylated during mitosis. siRNA-mediated knockdown of hBora led to spindle formation defects and aneuploidy. hBora overexpression caused monoastral spindle formation and mislocalization not only of Aurora A but also Plk1. Further investigations showed that Cdk1 phosphorylation on hBoraSer252 leads to Plk1 binding and this may promote the SCF-mediated proteolysis of hBora. Indeed, Plk1 depletion led to an increase in hBora levels. Interestingly, the co-depletion of both hBora and Plk1 (to lower hBora levels in Plk1 depleted cells) rescued the localization of Aurora A to the centrosomes and bipolar spindle formation. Thus, we propose that hBora is a functional link between Plk1 and Aurora A and that by modulating the proteolysis of hBora, Plk1 could regulate Aurora A localization and activity. At the end, we also investigated the function of Aurora A and could show that Aurora A is required for centriole cohesion and centrosome separation.

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06
Untersuchungen zur funktionellen Äquivalenz zwischen Notch und EBNA2 in EBV-immortalisierten B-Zellen

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06

Play Episode Listen Later Jan 29, 2007


Notch-Signale spielen bei der Entwicklung von Lymphozyten eine wichtige Rolle. So induzieren Notch1-Signale in Lymphozyten-Vorläuferzellen im Knochenmark die Entwicklung zu T-Zellen, während Notch2-Signale essentiell für die Differenzierung reifer B-Zellen zu Marginalzonen-B-Zellen sind. Das Epstein-Barr Virus (EBV) infiziert reife B-Zellen und regt diese zur permanenten Proliferation an. EBNA2, das erste Protein, das in EBV-infizierten B-Zellen exprimiert wird, verwendet zur Regulation von Zielgenen den gleichen Signalweg wie Notch und wird deshalb als (partielles) funktionelles Äquivalent eines aktivierten Notch-Rezeptors (NotchIC) bezeichnet. Notch und EBNA2 können sich bezüglich der Muskelzelldifferenzierung gegenseitig ersetzen, die Proliferation in B-Zellen kann dagegen nur EBNA2 induzieren. Ziel dieser Arbeit war es zu untersuchen, mit Hilfe welcher Zielgene Notch und EBNA2 unterschiedliche und gemeinsame Funktionen vermitteln. Zu diesem Zweck wurde ein Zellsystem etabliert, bei dem Tetrazyclin-regulierbares aktives Notch1IC oder Notch2IC in humane reife EBV-immortalisierte B-Zellen eingebracht wurde. In diesem System konnten Notch1IC oder Notch2IC in Abwesenheit von EBNA2 exprimiert werden, sowie EBNA2 in Abwesenheit von NotchIC. Die Expression von Zielgenen wurde anhand einer Microarray- Analyse untersucht. Damit sollten Notch1IC-, Notch2IC- und EBNA2-regulierte Zielgene identifiziert werden. Hierbei wurde vornehmlich auf Unterschiede und Gemeinsamkeiten zwischen Notch1IC- und Notch2IC-regulierten Genen, sowie zwischen NotchIC- und EBNA2-regulierten Genen eingegangen. Durch Notch1IC wurden 270 Gene induziert und 374 Gene reprimiert. Notch2IC konnte 757 Gene induzieren und 959 Gene reprimieren. EBNA2 induzierte 6.250 Gene und reprimierte 6.811 Gene. Die Auswertung der Zielgene in der Clusteranalyse ergab, dass viele Gene reguliert wurden, die mit dem Zellzyklus und der Immunmodulation assoziiert sind. Aus diesem Grund sollten diese beiden Signalwege näher untersucht werden. In dem beschriebenen Zellsystem konnten weder Notch1IC noch Notch2IC die EBNA2-vermittelte Proliferation ersetzen. So konnten Notch1IC und Notch2IC zwar einige Zellzyklus-Gene induzieren, die aber assoziierten eher mit der S-Phase und mit der Mitose. Die von EBNA2 stark induzierten Gene c-Myc und LMP1, sowie die G1-Phase assoziierten D-Cycline und der Cyclin-abhängigen Kinasen CDK4 und CDK6 konnten durch NotchIC nicht oder nur schwach induziert werden. Vermutlich können Notch1IC und Notch2IC die Proliferation weder aufrechterhalten noch induzieren, da sie nicht fähig sind, G1-Phase Gene, sowie c-Myc und LMP1 ausreichend stark zu induzieren. Der Einfluss von NotchIC auf die Immunmodulation war mit der von EBNA2 vergleichbar. Die Repression vieler Gene, die mit der Immunmodulation assoziieren, weist darauf hin, dass sowohl Notch1IC, Notch2IC als auch EBNA2 die Immunantwort negativ regulieren. So könnten B-Zellrezeptor (BCR)-Signale über die Repression von Komponenten und Signalmolekülen des BCR abgeschwächt werden, die Antigenpräsentation über die Repression von MHC-Molekülen vermindert werden und der allgemeine Aktivierungszustand zusätzlich über die Repression von Komplement-, Toll-like- und Fc-Rezeptoren vermindert werden. Ebenso konnte gezeigt werden, dass Notch1IC, Notch2IC und EBNA2 den Klassenwechsel negativ beeinflussen. Dies wird möglicherweise über die transkriptionelle Repression der Interleukin-Rezeptoren IL4Rα1 und IL13Rα1, sowie über die Modulation von Molekülen des Signalwegs vermittelt, die die Expression von sterilen Transkripten induzieren und somit die Voraussetzung zum Klassenwechsel bilden.

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06
Funktion und Regulation von Separase in Vertebraten

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06

Play Episode Listen Later Aug 14, 2006


Um Aneuploidie zu verhindern, muss die Trennung der Chromosomen in der Anaphase mit hoher Genauigkeit und daher streng reguliert ablaufen. Bisher galt folgendes Modell der eukaryontischen Schwesterchromatidentrennung: Der „anaphase promoting complex/cyclosome” (APC/C) wird erst aktiviert, wenn alle Chromosomen ordnungsgemäß bipolar an die Mikrotubuli des Spindelapparates angeheftet sind. In seiner Eigenschaft als Ubiquitinligase katalysiert der APC/C dann den proteasomalen Abbau des Anaphaseinhibitors Securin aus dem Komplex mit Separase. Die auf diese Weise als Protease aktivierte Separase löst daraufhin die Anaphase aus, indem sie den Proteinkomplex Kohäsin, welcher die Schwesterchromatiden zusammenhält, spaltet. Das Ausbleiben eines Phänotyps beim Verlust von Securin deutet jedoch auf die Existenz weiterer Regulationsmechanismen der Anaphase hin. Der APC/C sorgt gleichermaßen für den Abbau von Cyclin B1. Die damit verbundene Inaktivierung der Cyclin-abhängigen Kinase 1 (Cdk1) führt zum Austritt aus der Mitose. Im Gegensatz zur Bäckerhefe, in der die Cdc14-Phosphatase ebenfalls als essentieller Gegenspieler von Cdk1 fungiert, repräsentierte in höheren Eukaryonten der APC/C-abhängige Abbau von Cyclin B1 den einzig bekannten Mechanismus zur Cdk1-Inaktivierung. Bisher glaubte man, dass nach dem APC/C die zur Anaphase und zum Mitoseaustritt führenden Signalwege strikt getrennt voneinander verlaufen. Daher war die kürzlich gemachte Beobachtung unerwartet, wonach die durch nicht abbaubares Cyclin B1 konstitutiv aktivierte Cdk1-Kinase die Schwesterchromatidentrennung in Xenopus Eiextrakten blockiert und zwar durch eine Securin-unabhängige Inhibition von Separase. Obwohl die Mutation von Separase an Cdk1-Phosphorylierungsstellen die Kohäsinspaltung in Gegenwart von aktiver Cdk1 wiederherstellte, blieben die molekularen Details der Cdk1-abhängigen Separaseinhibition unklar. In der vorliegenden Arbeit wird gezeigt, dass die Phosphorylierung zwar notwendig aber nicht hinreichend ist, um Separase zu inaktivieren. Zur Inhibition kommt es erst, wenn in einem zweiten Schritt der Cdk1-Komplex stabil und unabhängig von seiner Kinaseaktivität an zuvor phosphorylierte Separase bindet. Es wurde eine Region in Separase identifiziert, die wahrscheinlich in Abhängigkeit von ihrer Phosphorylierung durch die regulatorische Cyclin B1-Untereinheit von Cdk1 erkannt wird. Da sich Securin- und Cdk1-Bindung an Separase gegenseitig ausschließen, stellen sie, anders als ursprünglich angenommen, nicht konvergente sondern parallele Inhibitions-mechanismen dar. Bei der Rekonstitution des Separase-Cdk1 Komplexes wurde eine neue Funktion von Vertebraten-Separase als ein direkter, stöchiometrischer Cdk1-Inhibitor entdeckt, welche unabhängig von der proteolytischen Aktivität ist. Eine durch Mutantenanalyse verifizierte Sequenzhomologie im Cyclin B-bindenden Bereich zwischen Separase und dem Cdk1-Inhibitor Cdc6 aus S. cerevisiae bestätigt dieses Ergebnis. Mikroinjektionsexperimente an Oozyten zeigen, dass die Separase-vermittelte Inhibition von Cdk1 eine essentielle Rolle während der Meiose I spielt. Separase ist also nicht nur ein universeller Auslöser der eukaryontischen Anaphase, sondern sie wirkt auch, trotz unterschiedlicher Mechanismen in Hefe und Vertebraten, als konservierter Cdk1-Antagonist und koppelt damit die Anaphase mit dem Austritt aus der Meiose I.

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06
Posttranslationale Modifikation des Retinoblastoma Tumorsuppressors mit dem Ubiquitin-ähnlichen SUMO Protein

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06

Play Episode Listen Later Jul 20, 2006


Abläufe in der Zelle eines multizellulären Organismus im Rahmen des Zellzyklus oder beim Vorgang der Differenzierung unterliegen strengen Kontrollmechanismen. Ein prominentes Regulationsprotein dieser Mechanismen ist der Retinoblastoma Tumorsuppressor (pRB). Im Zellzyklus liegt die Hauptfunktion pRBs in der Kontrolle des Übergangs von der G1- in die S-Phase. In der aktiven, nichtphosphorylierten Form reprimiert pRB die Expression von S-Phase Genen durch Inaktivierung des Transkriptionsfaktors E2F. Cyclin-abhängige Kinasen überführen pRB in eine mehrfach phosphorylierte, inaktive Form, wodurch die S-Phase eingeleitet wird. Im Gegensatz dazu übt pRB bei Differenzierungsvorgängen aber auch koaktivierende Funktionen aus und wird im Rahmen dieser Prozesse acetyliert. In der vorliegenden Arbeit konnte gezeigt werden, dass pRB nicht nur phosphoryliert und acetyliert wird, sondern darüber hinaus durch den small ubiquitin-like modifier (SUMO) modifiziert wird. Aktives pRB stellt das bevorzugte Substrat dieser Modifikation dar. Das Akzeptorlysin 720 ist konserviert und liegt in einer für die pRB-Funktion entscheidenden Domäne, der sogenannten pocket B Region. Zusammen mit der pocket A Region bildet sie die pocket Domäne, deren strukturelle Integrität sowohl für die Tumorsuppressorfunktion pRBs als auch für die Modifikation durch SUMO essenziell ist. An die pocket B Region binden neben zellulären Regulationsproteinen des Zellzyklus und der Differenzierung auch virale Onkoproteine, die pRB inaktivieren und dadurch für die Transformation einer Zelle verantwortlich sind. Diese viralen Onkoproteine und bestimmte zelluläre Proteine inhibieren die SUMO-Modifikation pRBs. Umgekehrt steigt die SUMOylierung von pRB an, wenn mutierte pRB-Versionen eingesetzt werden, die keine viralen oder zellulären Proteine mehr über die pocket B Region binden können. Eine Version von pRB, bei der das Lysin 720 zu Arginin ausgetauscht wurde und die somit nicht mehr SUMOyliert werden kann, besitzt ein stärkeres Repressionspotenzial auf die E2F-abhängige Genexpression, wie Reportergenversuche zeigten. Die SUMOylierung vermindert also pRBs Potenzial zur E2F-Reprimierung. Möglicherweise wird durch die SUMO-Modifikation von pRB die Zusammensetzung der Bindungspartner an der wichtigen pocket B Region moduliert.

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06
Structure of the Mediator subunit Cyclin C and subunit interaction studies within the Mediator head module

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06

Play Episode Listen Later Oct 27, 2005


The Mediator of transcriptional regulation is the central coactivator that enables a response of RNA polymerase II to activators and repressors. It is conserved from yeast to human and consists of 25 subunits in yeast that are organized in four modules called head, middle, tail, and CDK8/Cyclin C module. Despite its central role in transcription the functional mechanism remains enigmatic. To overcome the lack of detailed structural data on the Mediator a recombinant expression system was established that allows large-scale purifications of Mediator head module subcomplexes. It has been shown that via limited proteolysis assays and multicistronic expression the problems of insolubility and low expression rates of Mediator subunits can be overcome, paving the way for structural studies on subcomplexes of the Mediator head module. First data indicated that a reconstitution of the complete head module is within close reach. Large-scale copurification data led to a detailed interaction map of subunits and subcomplexes from within the head module and towards the middle module. The second part of this work describes the structure solution of a subunit in the CDK8/Cyclin C module – Cyclin C. Cyclin C binds the cyclin-dependent kinases CDK8 and CDK3, which regulate mRNA transcription and the cell cycle, respectively. The crystal structure of Cyclin C reveals two canonical five-helix repeats and a specific N-terminal helix. In contrast to other cyclins, the N-terminal helix is short, mobile, and in an exposed position that allows for interactions with proteins other than the CDKs. A model of the CDK8/Cyclin C pair reveals two regions in the interface with apparently distinct roles. A conserved region explains promiscuous binding of cyclin C to CDK8 and CDK3, and a non-conserved region may be responsible for discrimination of CDK8 against other CDKs involved in transcription. A conserved and Cyclin C-specific surface groove may recruit substrates near the CDK8 active site. Activation of CDKs generally involves phosphorylation of a loop at a threonine residue. In CDK8, this loop is longer and the threonine is absent suggesting an alternative mechanism of activation is discussed based on a CDK8-Cyclin C model.