Effects of fasting on gene expression from livers with or without Mcl1 genetic deletion
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE225055 | GEO | 2024/03/19
REPOSITORIES: GEO
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Project description:T cell differentiation is governed by interactions with thymic epithelial cells (TECs) and defects in this process undermine immune function and tolerance. To uncover new strategies to restore thymic function and adaptive immunity in immunodeficiency, we sought to determine the molecular mechanisms that control life and death decisions in TEC. We created a mouse model which specifically deleted the pro-survival gene Mcl1 in TEC. We found that while BCL-2 and BCL-XL were dispensable for TEC homeostasis, MCL-1 deficiency impacted on TEC as early as E15.5, resulting in early thymic atrophy and T cell lymphopenia, with near complete loss of thymic tissue by 2 months of age. MCL-1 was not necessary for TEC differentiation but was continually required for the survival of medullary TEC, including autoimmune regulator (AIRE) expressing TECs and the maintenance of overall thymic architecture. To understand the molecular mechanisms in more detail, RNA-seq profiling was undertaken of cortical and medullary thymic epithelial cells (cTECs and mTECs) from wildtype and knockout mice.
2017-09-25 | GSE102227 | GEO
Project description:Effects of fasting on gene expression from livers with or without Mcl1 genetic deletion
| PRJNA933619 | ENA
Project description:The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in protecting CSCs from cell death, where its inhibition with high doses of BH3-mimetics can induce apoptosis. To identify pathways that can regulate sensitivity to BCL-XL inhibition, we screened a compound library for synergy with low dose BCL-XL inhibitor A-1155463 and reveal that FGFR4 inhibition effectively sensitizes to A-1155463 both in vitro and in vivo. Mechanistically, we identify a rescue response that is activated upon BCL-XL inhibition and leads to rapid FGF2 secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1. FGFR4 inhibition prevents MCL-1 upregulation and thereby sensitizes CSCs to BCL-XL inhibition. Altogether, our findings suggest a cell transferable induction of a FGF2/FGFR4 rescue response in CRC that is induced upon BCL-XL inhibition and leads to MCL-1 upregulation.
2021-12-22 | GSE159504 | GEO
Project description:Glioblastomas harbor a super-enhancer at the MCL1 locus, which translates to increased MCL1 levels as compared to normal brain tissue. While suppression of Mcl-1 alone did not yield in significant apoptosis induction, combined inhibition of Bcl-xL/Bcl-2 along with Mcl-1 led to strong cell killing and reduction of tumor growth in patient-derived xenograft models in vivo.
2020-05-22 | GSE150986 | GEO
Project description:MicroRNAs (miRNAs) have important roles in gene regulation. Dysregulation of miRNAs has been associated with tumorigenesis. Recent studies suggest miR-193b is a tumor suppressor gene. In a previous study, we reported that miR-193b represses cell proliferation and regulates cyclin D1 (CCND1) in melanoma. Now we demonstrate that miR-193b regulates myeloid cell leukemia sequence 1 (Mcl-1) in melanoma cells. miRNA microarray profiling revealed the miR-193b level in malignant melanomas was significantly downregulated compared to benign nevi, while a tissue microarray demonstrated overexpression of Mcl-1 in malignant melanoma. The Mcl-1 expressions were inversely correlated with the miR-193b levels in melanoma tissue samples, suggesting a potential regulatory role of miR-193b. Overexpression of miR-193b repressed Mcl-1 in melanoma cell lines. It is well known that Mcl-1 knockdown confers cell sensitivity to ABT-737, a small molecular inhibitor of Bcl-2, Bcl-XL and Bcl-w. We found miR-193b, through repressing Mcl-1 expression, could also sensitize melanoma cells that were refractory to ABT-737. Furthermore, miR-193b directly regulates Mcl-1 by targeting the 3â untranslated region (3âUTR) of Mcl-1 mRNA. Interestingly, miR-193b may recognize sequences on the 3âUTR that do not base pair with its seed region. In conclusion, our study suggests the downregulation of miR-193b could be an early event during melanoma progression, and demonstrates miR-193b directly regulates Mcl-1 by targeting both seed and seedless sequences of the 3â UTR. 15 primary melanoma samples, 8 metastatic melanomas and 8 benign nevi samples were profiled on Agilent miRNA array platform
2010-10-30 | E-GEOD-24996 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) have important roles in gene regulation. Dysregulation of miRNAs has been associated with tumorigenesis. Recent studies suggest miR-193b is a tumor suppressor gene. In a previous study, we reported that miR-193b represses cell proliferation and regulates cyclin D1 (CCND1) in melanoma. Now we demonstrate that miR-193b regulates myeloid cell leukemia sequence 1 (Mcl-1) in melanoma cells. miRNA microarray profiling revealed the miR-193b level in malignant melanomas was significantly downregulated compared to benign nevi, while a tissue microarray demonstrated overexpression of Mcl-1 in malignant melanoma. The Mcl-1 expressions were inversely correlated with the miR-193b levels in melanoma tissue samples, suggesting a potential regulatory role of miR-193b. Overexpression of miR-193b repressed Mcl-1 in melanoma cell lines. It is well known that Mcl-1 knockdown confers cell sensitivity to ABT-737, a small molecular inhibitor of Bcl-2, Bcl-XL and Bcl-w. We found miR-193b, through repressing Mcl-1 expression, could also sensitize melanoma cells that were refractory to ABT-737. Furthermore, miR-193b directly regulates Mcl-1 by targeting the 3’ untranslated region (3’UTR) of Mcl-1 mRNA. Interestingly, miR-193b may recognize sequences on the 3’UTR that do not base pair with its seed region. In conclusion, our study suggests the downregulation of miR-193b could be an early event during melanoma progression, and demonstrates miR-193b directly regulates Mcl-1 by targeting both seed and seedless sequences of the 3’ UTR.
2010-10-30 | GSE24996 | GEO
Project description:Many traditional cytotoxic agents used in the treatment of cancer function by eliciting an apoptotic response in tumor cells. However, evasion of apoptosis by BCL-2 family members is often deregulated prior to therapeutic intervention leading to treatment failure. To address this, ABT-737 was rationally designed to target BCL-2-like family members and has shown promising results against tumor cells dependent on BCL-2 for their survival. One shortcoming is that MCL-1, a member of the BCL-2 family is poorly inhibited by ABT-737 and is a major cause of resistance. To gain insight into biological pathways that could circumvent this resistance, we designed an shRNA screen to identify novel sensitizers to ABT-737 by engineering MYC driven lymphomas that were resistant to ABT-737 due to endogenous MCL-1 expression. Utilizing this model, we performed a shRNA drop-out screen and identified Dhx9 as a target whose suppression sensitizes cells to ABT-737. DHX9 loss lead to replicative stress signaling, which in turn potently induced the BH3-only proteins, NOXA and PUMA, in a p53-dependent manner to curtail MCL-1 activity. Induction of NOXA is essential for ABT-737 sensitization. Our results ascribe a novel role for DHX9 in the replicative stress pathway and link DHX9 activity to p53 function in vivo. Comparison of Arf-/-Eu-myc/Bcl-2 lymphomas expressing either control Rluc.713 or Dhx9 shRNA, Dhx9.1241
2013-04-03 | E-GEOD-36938 | biostudies-arrayexpress
Project description:Mantle cell lymphoma (MCL) accumulates in lymphoid organs but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies have assessed MCL microenvironment. We therefore cocultured primary circulating MCL cells from 21 patients several weeks ex vivo with stromal or lymphoid-like (CD40L) cells to determine which interactions could support proliferation of MCL cells. We showed that coculture with lymphoid-like cells, but not stromal cells, induced cell-cycle progression, which was amplified by MCL-specific cytokines (IGF-1, BAFF, IL-6, IL-10). Of interest, we showed that our model recapitulated the MCL in situ molecular signatures i.e., proliferation, NFkB and survival signatures. We further demonstrated that proliferating MCL harbored an imbalance in Bcl-2 family expression leading to a consequent loss of mitochondrial priming. Interestingly, this loss of priming was overcome by the Type II anti-CD20 antibody obinutuzumab, which counteracted Bcl-xL induction through NFkB inhibition. Finally, we showed that the mitochondrial priming directly correlated with the sensitivity toward venetoclax and alkylating drugs. By identifying the microenvironment as the major support for proliferation and drug resistance in MCL, our results highlight a selective approach to target the lymphoma niche.
2017-01-02 | GSE86322 | GEO
Project description:MCL-1 is an anti-apoptotic BCL-2 family protein essential to the survival of diverse cell types and is a major driver of cancer and chemoresistance. The unique oncogenic supremacy of MCL-1, as compared to its anti-apoptotic homologs, suggests that it has additional functions to complement apoptotic suppression. Here, we find that MCL-1-dependent hematologic cancer cells selectively rely on fatty acid oxidation (FAO) as a fuel source due to metabolic wiring enforced by MCL-1 itself. Importantly, this metabolic function is independent of anti-apoptotic activity, as demonstrated by metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking pro-apoptotic BAX and BAK. Genetic deletion of Mcl-1 results in selective downregulation of proteins within the FAO pathway, accompanied by cell death upon glucose deprivation despite apoptotic blockade. Our data reveal that MCL-1 drives a programmatic dependency on FAO in hematologic cancer cells, which can be effectively targeted by FAO inhibitors.
2022-10-03 | PXD031364 | Pride
Project description:MCL-1 is an anti-apoptotic BCL-2 family protein essential for survival of diverse cell types and is a major driver of cancer and chemoresistance. The mechanistic basis for the oncogenic supremacy of MCL-1 among its anti-apoptotic homologs is unclear and implicates physiologic roles of MCL-1 beyond apoptotic suppression. Here we find that MCL-1-dependent hematologic cancer cells specifically rely on fatty acid oxidation (FAO) as a fuel source because of metabolic wiring enforced by MCL-1 itself. We demonstrate that FAO regulation by MCL-1 is independent of its anti-apoptotic activity, based on metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking an intact apoptotic pathway. Genetic deletion of Mcl-1 results in transcriptional downregulation of FAO pathway proteins such that glucose withdrawal triggers cell death despite apoptotic blockade. Our data reveal that MCL-1 is a master regulator of FAO, rendering MCL-1-driven cancer cells uniquely susceptible to treatment with FAO inhibitors.
2022-10-04 | GSE196136 | GEO