Podcasts about c ebp

BUFFALO, NY- November 13, 2023 – A new #editorial perspective was #published in Oncotarget's Volume 14 on March 11, 2023, entitled, “C/EBPβ cooperates with MYB to maintain the oncogenic program of AML cells.” In this new paper, researcher Karl-Heinz Klempnauer from Westfälische-Wilhelms-Universität discusses recent studies on the role of transcription factor MYB in acute myeloid leukemia (AML). MYB has been identified as a key regulator of a transcriptional program for self-renewal of AML cells. The MYB gene initially attracted attention as the progenitor of a retrovirally-transduced oncogene that induces a myeloid leukemia in chicken [1–4]. MYB encodes a transcription factor with essential roles in the development of the hematopoietic system [5] and the proliferation and differentiation of hematopoietic progenitor cells [6]. Subsequent work identified MYB also as a crucial player in the development and maintenance of leukemia in humans. “Recent work summarized here has now highlighted the CCAAT-box/enhancer binding protein beta (C/EBPβ) as an essential factor and potential therapeutic target that cooperates with MYB and coactivator p300 in the maintenance of the leukemic cells.” DOI - https://doi.org/10.18632/oncotarget.28377 Correspondence to - Karl-Heinz Klempnauer - klempna@uni-muenster.de Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28377 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, MYB, C/EBPbeta, p300, GFI1, AML 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

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.14.520351v1?rss=1 Authors: Buckwalter, M. S., Hernandez, V. G., Lechtenberg, K. J., Peterson, T. C., Zhu, L., Lucas, T. A., Owah, J. O., Dorsey, A. I. Abstract: Neuroinflammation is a hallmark of ischemic stroke, which is a leading cause of death and long-term disability. Understanding the exact cellular signaling pathways that initiate and propagate neuroinflammation after stroke will be critical for developing immunomodulatory stroke therapies. In particular, the precise mechanisms of inflammatory signaling in the clinically relevant hyperacute period hours after stroke have not been elucidated. We used the RiboTag technique to obtain astrocyte and microglia-derived mRNA transcripts in a hyperacute (4 hours) and acute (3 days) period after stroke, as these two cell types are key modulators of acute neuroinflammation. Microglia initiated a rapid response to stroke at 4 hours by adopting an inflammatory profile associated with the recruitment of immune cells. The hyperacute astrocyte profile was marked by stress response genes and transcription factors, such as Fos and Jun, involved in pro-inflammatory pathways such as TNF-. By 3 days, microglia shift to a proliferative state and astrocytes strengthen their inflammatory response. The astrocyte pro-inflammatory response at 3 days may be driven by the upregulation of the transcription factors C/EBP{beta}, Spi1, and Rel, which comprise 25% of upregulated transcription factor-target interactions. Surprisingly, few sex differences across all groups were observed. Expression and log2 fold data for all sequenced genes are available on a user-friendly website for researchers to examine gene changes and generate hypotheses for stroke targets. Taken together our data comprehensively describe the astrocyte and microglia-specific translatome response in the hyperacute and acute period after stroke and identify pathways critical for initiating neuroinflammation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.09.507328v1?rss=1 Authors: Stephens, K. E., Moore, C., Vinson, D. A., White, B. E., Renfro, Z., Zhou, W. E., Ji, Z., Ji, H., Zhu, H., Guan, Y., Taverna, S. Abstract: Chronic pain is a significant public health issue that is often refractory to existing therapies. Here we use a multiomic approach to identify cis-regulatory elements that show differential chromatin accessibility, and reveal transcription factor (TF) binding motifs with functional regulation in the dorsal root ganglion (DRG), which contain cell bodies of primary sensory neurons, after nerve injury. We integrated RNA-seq to understand how differential chromatin accessibility after nerve injury may influence gene expression. Using TF protein arrays and chromatin immunoprecipitation-qPCR, we confirmed C/EBP{gamma} binding to a differentially accessible sequence and used RNA-seq to identify processes in which C/EBP{gamma} plays an important role. Our findings offer insights into TF motifs that are associated with chronic pain. These data show how interactions between chromatin landscapes and TF expression patterns may work together to determine gene expression programs in DRG neurons after nerve injury. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Aging-US published a Special Collection on Eye Disease which included "ALDH2 protects naturally aged mouse retina via inhibiting oxidative stress-related apoptosis and enhancing unfolded protein response in endoplasmic reticulum" which reported that during the process of aging, the retina exhibits chronic oxidative stress damage. These authors' preliminary experiment showed that acetaldehyde dehydrogenase 2 could alleviate retinal damage caused by OS. Retinal function and structure in vivo and in vitro were examined in aged ALDH2+ overexpression mice and ALDH2 agonist Alda1-treated aged mice. Levels of ALDH2, endoplasmic reticulum stress, apoptosis and inflammatory cytokines were evaluated. Moreover, aged ALDH2+ overexpression mice and aged Alda1-treated mice exhibited better retinal function and structure. Increased expression of glucose-regulated protein 78 and ERS-related protein phosphorylated eukaryotic initiation factor 2 and decreased expression of apoptosis-related protein, including C/EBP homologous protein, caspase12 and caspase9, and retinal inflammatory cytokines were detected in the retina of aged ALDH2+ overexpression mice and aged Alda1-treated mice. Dr. Tao Chen and Dr. Wei Ge said, "The aging process is characterized by a decline in systematic tissue function and the onset of serious of age-related disease." However, it remained elusive that the potential mechanisms accounting for these phenomena and strategies to intervene to improve cell functions. Recently, the imbalance of protein homeostasis was proposed to be responsible for aging and age-related diseases. Furthermore, eukaryotic translation initiation factor 2, a protein translation component, is the downstream of PERK. When endoplasmic reticulum stress happens, eIF2 is phosphorylated to slow down protein production and reduce the unfolded and misfolded proteins. Nevertheless, the underlying mechanisms of UPRER related to aged retinal behaviour remain largely unclear, and effective therapies to intervene in aging-related injury to the retina by targeting the UPRER have not been developed. Mitochondrial aldehyde dehydrogenase 2 is essential for the catabolism of exogenous and endogenous toxic aldehydes associated with oxidative stress-induced lipid peroxidation and adducts with DNA, RNA and protein. The Chen/Ge Research Team concluded in their Aging-US Research Output, "overexpression of ALDH2 and treatment with the ALDH2 agonist Alda1 in aging mice could both result in good retinal function and structural integrity via attenuating oxidative stress and apoptosis, and enhancing UPRER. Therefore, an increasing expression of ALDH2 could serve to preserve retinal function during the normal aging process or the onset of age-related retinal disease." Full Text - https://www.aging-us.com/article/202325/text Correspondence to: Tao Chen email: ct1988@fmmu.edu.cn and Wei Ge email: geweidr@fmmu.edu.cn Keywords: ALDH2, UPRER, retina, aged mice, oxidative stress About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways. To learn more about Aging-US, please visit http://www.Aging-US.com or connect with @AgingJrnl Aging-US is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact 18009220957x105 MEDIA@IMPACTJOURNALS.COM

The cover for issue 26 of Oncotarget features Figure 8, "Proposed mechanism of action of ONC201," from Greer, et al. TRAIL, a member of the TNF family of ligands, causes caspase–dependent apoptosis through activation of its receptors, death receptor 4 and DR5. ONC201 was originally identified as a small molecule that inhibits both Akt and ERK, resulting in dephosphorylation of Foxo3a and thereby induces TRAIL transcription. Recently, two independent groups, Wafik El Deiry at Fox Chase and Michael Andreeff at MD Anderson,reported that ONC201 induces cell death via cell stress mechanisms, independent of TRAIL transcription. Gene expression profiling analysis revealed that ONC201 induces endoplasmic reticulum (ER) stress or integrated stress response –related genes, such as Activating Transcription Factor 4 (ATF4) and C/EBP–homologous protein (CHOP). The researchers in Dr. Lipkowitz's group at the Center for Cancer Research in the National Cancer Institute observed that ONC201 kills breast cancer cells via a TRAIL–independent mechanism. Time–lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. They found that ONC201 inhibits mitochondrial respiration and induces mitochondrial structural damage. Moreover, they found ONC201 reduces mitochondrial DNA copy number. Importantly, cells dependent on glycolysis, such as fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mitochondrial DNA were resistant to ONC201. ONC201 induced ATF4 and CHOP in breast cancer cells, and the stress response it was partially dependent on the mitochondrial effects of ONC201. "Our work identifies a novel mechanism of ONC201 cytotoxicity that is based on the disruption of mitochondrial function, leading to ATP depletion and cell death in cancer cells that are dependent on mitochondrial respiration. Our study also suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201" Dr. Stanley Lipkowitz, Chief, Women's Malignancies Branch, NCI. Full text – https://www.oncotarget.com/article/24... About Oncotarget Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com/ or connect with @Oncotarget Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact 18009220957x105 MEDIA@IMPACTJOURNALS.COM

Genome-wide association studies identified PTPN2 (protein tyrosine phosphatase, non-receptor type 2) as susceptibility gene for inflammatory bowel diseases (IBD). However, the exact role of PTPN2 in Crohn's disease (CD) and ulcerative colitis (UC) and its phenotypic effect are unclear. We therefore performed a detailed genotype-phenotype and epistasis analysis of PTPN2 gene variants. Genomic DNA from 2131 individuals of Caucasian origin (905 patients with CD, 318 patients with UC, and 908 healthy, unrelated controls) was analyzed for two SNPs in the PTPN2 region (rs2542151, rs7234029) for which associations with IBD were found in previous studies in other cohorts. Our analysis revealed a significant association of PTPN2 SNP rs2542151 with both susceptibility to CD (p = 1.95×10⁻⁵; OR 1.49 [1.34-1.79]) and UC (p = 3.87×10⁻², OR 1.31 [1.02-1.68]). Moreover, PTPN2 SNP rs7234029 demonstrated a significant association with susceptibility to CD (p = 1.30×10⁻³; OR 1.35 [1.13-1.62]) and a trend towards association with UC (p = 7.53×10⁻²; OR 1.26 [0.98-1.62]). Genotype-phenotype analysis revealed an association of PTPN2 SNP rs7234029 with a stricturing disease phenotype (B2) in CD patients (p = 6.62×10⁻³). Epistasis analysis showed weak epistasis between the ATG16L1 SNP rs2241879 and PTPN2 SNP rs2542151 (p = 0.024) in CD and between ATG16L1 SNP rs4663396 and PTPN2 SNP rs7234029 (p = 4.68×10⁻³) in UC. There was no evidence of epistasis between PTPN2 and NOD2 and PTPN2 and IL23R. In silico analysis revealed that the SNP rs7234029 modulates potentially the binding sites of several transcription factors involved in inflammation including GATA-3, NF-κB, C/EBP, and E4BP4. Our data confirm the association of PTPN2 variants with susceptibility to both CD and UC, suggesting a common disease pathomechanism for these diseases. Given recent evidence that PTPN2 regulates autophagosome formation in intestinal epithelial cells, the potential link between PTPN2 and ATG16L1 should be further investigated.

Tue, 11 Nov 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/10298/ https://edoc.ub.uni-muenchen.de/10298/1/Pulikkan_John-Anto.pdf Pulikkan, John Anto

Thu, 18 Oct 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7556/ https://edoc.ub.uni-muenchen.de/7556/1/Franz_Steffen.pdf Franz, Steffen

The transcription factor C/EBPα is a key player in granulopoiesis and leukemogenesis. In the present study, we sought to identify C/EBPα interacting proteins. A glutathione-S-transferase-C/EBPα fusion protein was used to pull down interacting proteins from U937 nuclear extracts. These proteins were analyzed by 2-D gel electrophoresis or 1-D nano LC and identified by mass spectrometry. The interaction between C/EBPand two novel interacting partners, the cell cycle regulator protein MCM5 and the MYST domain histone aceyltransferase TIP60, was confirmed by using pull-down and co-immunoprecipitation experiments. TIP60 was able to markedly enhance C/EBPα mediated transcriptional activation in reporter gene assays, suggesting that TIP60 is a co-activator of C/EBPα. This co-activator function of TIP60 was dependent on its intact histone aceyltransferase domain and on the C/EBPα DNA binding domain. TIP60 was found to be associated with the human C/EBPα promoter in vivo in a chromatin immunoprecipitation assay with a concomitant increase in histone H3 and H4 acetylation. Furthermore, we observed a lower expression of TIP60 mRNA in undifferentiated U937 CD11b- cells compared to retinoic acid induced differentiated U937 CD11b+ cells suggesting that higher TIP60 expression is associated with myeloid differentiation. Correlated expression between C/EBP and TIP60 was also observed in certain leukemia subtypes. These findings point to a functional synergism between C/EBP and TIP60 in myeloid differentiation and suggests that TIP60 might be an important player in leukemogenesis.

Acute Myeloid Leukemia (AML) is characterized by specific cytogenetic aberrations that are strong determinants of prognostic outcome and therapeutic response. Because the pathological outcome of AML patients with cytogentic abnormalities differs considerably we hypothesized that their proteome may also differ specifically in their expression pattern, protein interaction pathways and posttranslational modifications. We performed this study using 42 AML patients diagnosed for various cytogenetic abnormalities based on two-dimensional gel electrophoresis and MALDI TOF Tandem MS (MS/MS) analysis. We could identify significant differences in the proteome and posttranslational modifications of peptides, later confirmed by other methods, between cytogenetic groups. The interactome analysis based on computational bioinformatics reveals a major regulating networks, MAPK8 and MYC for complex aberrant karyotype, TP53 for t(8;21), TP53- MYC- PRKAC for 11q23, JUN and MYC for Inv(16). We could show in our validation and characterisation experiments that survivin is a novel target of t(8;21) leukemia and AML1-ETO directly regulates its expression to induce the differentiation block that could be overcome by silencing its expression. Further, we analysed 42 MS spectra representative of hnRNPH1, Calreticulin and hnRNPA2/B1 in a peak explorer which reveals a cytogenetic specific posttranslational modification of β-O-linked N-acetyl glucosamine (O-GlcNAc) of hnRNPH1 in AML patients with 11q23 translocation, an acetylation of calreticulin in t(8;21) translocation and methylation of hnRNPA2/B1 in patients with translocations of t(8;21) and inv(16). This report may lead to a new thinking about the AML pathogenesis as differences at PTM level could be used to distinguish different subtypes of AML besides for testing the therapeutic significance. Further, we characterised the biological role of survivin identified specifically from t(8;21) patients. We could show that AML1-ETO induces the expression of survivin both in a cell line model and in primary human hematopoietic precursors. AML1-ETO activates the basal transcription of the survivin promoter and binds to the only AML1 core enhancer binding sequence, TGTGGT, in survivin promotor. Repression of AML1-ETO mediated induction of survivin expression by a specific short hairpin RNA restores C/EBPα protein and its basal transcriptional activity on its own promotor. This restoration differentiates AML1-ETO positive leukemic cells to terminal granulocytic differentiation and growth arrest. These observations indicate that the antiapoptotic survivin protein, which holds a great therapeutic promise, is a critical mediator of AML1-ETO induced defective granulopoiesis. Thus, proving that AML1-ETO induces inhibition of granulocytic differentiation by activating survivin expression

Functional inactivation of the transcription factor CAAT Enhancer Binding Protein Alpha (C/EBPα) either by mutation or direct protein-protein interaction leads to acute myeloid leukemia (AML), whereas the activation of C/EBPα restores normal myeloid cell differentiation. We and others have shown that protein-protein interactions of C/EBPα play a pivotal role in myeloid differentiation and AML. In the present study we applied proteomics based mass spectrometry to identify C/EBPα interacting proteins on a proteome-wide scale. For this, the GST and GST-DNA binding domain of C/EBP (GST-DBD) was incubated with nuclear extracts of U937 cells. Interacting proteins separated by two-dimensional gel electrophoresis were identified by MALDI-TOF mass spectrometry. Using this approach we could identify PAK6, MADP-1, ZNF45 and the c-Jun N-terminal kinase 1 (JNK1) as C/EBPα interacting proteins. Since JNK1 activates c-Jun, the contra-player for C/EBPα, we hypothesized that the JNK1 and C/EBPα interaction might have some biological relevance. We could show that JNK1 binds to the DNA binding domain of C/EBP in GST-pull-down and to the C/EBPα in co-immunoprecipitation assays in-vitro and in-vivo respectively. JNK1 phosphorylates and increases the half life of the C/EBPα protein via inhibiting its ubiquitination and thereby enhances its transactivation and DNA binding activity. Furthermore, JNK mRNA expression as well as its kinase activity is lower in the AML patients in comparison to normal bone marrow mononuclear cells which implicates a possible mechanism of C/EBPα inactivation in certain acute myeloid leukemia subtypes. Thus our data suggest that a JNK activity is required for C/EBPα activation in myeloid cells and a loss of JNK regulated C/EBPα expression may contribute to leukemogenesis.