Mediator MED23 induces premature senescence by interacting with BCLAF1 via blocking autophagy flux in lung cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA597226 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:macroautophagy/autophagy plays a key role in regulating the balance between cell survival and senescence during the progression of lung cancer. Med23 (also known as Sur2), a protein belonging to an evolutionarily conserved high-molecularmass complex composed of more than 20 distinct subunits, promotes the growth, metastasis , and migration of lung cancer cells and is overexpressed in multiple cancers. However, the function of MED23 in autophagy regulation remains unknown. Here, we observes that MED23 expression is significantly upregulated in a subset of cancer cells and reversely correlated with overall survival rates and clinical stage for lung cancer patients. Mechanistically, MED23 is found to interact with BCLAF1 (BCL-2-associated transcription factor 1, BTF) ,a nuclear protein that can induce apoptosis and autophagy. Moreover, BCLAF1 interacts with the promoter of NUPR1 and downregulates its expression. We further show that BCLAF1 and MED23 depletion inhibits autophagy and induces premature senescence in vitro. Remarkably, the expression of BCLAF1 and MED23 are negatively correlated with NUPR1 in the human lung cancer tissues and adjacent normal tissues. Collectively, our data reveal a physical and genetic interaction between BCLAF1 and MED23, suggesting that MED23 constitutes a molecular node in the regulatory network of autophagy and this pathway may be an important therapeutic target in lung cancer.
2019-12-23 | GSE142508 | GEO
Project description:To analysis TCR induced Med23-dependent gene expression programs in T cells, we have employed microarray expression profiling as a discovery platform to identify genes with the potential to be regulated by Med23 in unstimulated or stimulated T cells. Mice CD4 T cells from wildtype and Med23 knockout mice were left unstimulated or stimulated for 6 hr, and gene expression difference was identified among four samples. Expression of seven genes (Med23, IFNg, IL2, Egr2, c-Fos, c-Jun and Foxp1) was validated in the same RNA samples by real-time PCR. TCR induced Med23-dependent gene expression was measured after unstimulation or stimulation for 6 hr in wildtype and Med23 knockout CD4 T cells.
2014-08-27 | E-GEOD-60779 | biostudies-arrayexpress
Project description:we provide evidence that Med23 is involved in the regulation of adult hippocampal neurogenesis in mouse. Med23-deficient NSCs in the SGZ display faster self-renewal activity possibly by reducing cell cycle length, but neuroblasts, immature and mature new-born neurons are reduced.
2020-06-10 | GSE152113 | GEO
Project description:To analysis TCR induced Med23-dependent gene expression programs in T cells, we have employed microarray expression profiling as a discovery platform to identify genes with the potential to be regulated by Med23 in unstimulated or stimulated T cells. Mice CD4 T cells from wildtype and Med23 knockout mice were left unstimulated or stimulated for 6 hr, and gene expression difference was identified among four samples. Expression of seven genes (Med23, IFNg, IL2, Egr2, c-Fos, c-Jun and Foxp1) was validated in the same RNA samples by real-time PCR.
2014-08-27 | GSE60779 | GEO
Project description:K-RAS activating mutations occur frequently in non-small cell lung cancer (NSCLC), leading to aberrant activation of Ras-MAPK signaling pathway that contributes to the malignant phenotype. However, the development of Ras-targeted therapeutics remains challenging. Here, we show that MED23, a component of the multisubunit Mediator complex that is known to integrate signaling and gene activities, is selectively important for Ras-active lung cancer. By screening a large panel of human lung cancer cell lines with or without a Ras mutation, we found that Med23 RNAi specifically inhibits the proliferation and tumorigenicity of lung cancer cells with hyperactive Ras activity. Med23-deficiency in fibroblasts selectively inhibited the oncogenic transformation induced by Ras but not by c-Myc. Transcription factor ELK1, which is phosphorylated by MAPK for relaying the Ras signaling to MED23, was also required for the Ras-driven oncogenesis. Transcriptiome analysis revealed that MED23 and ELK1 co-regulate a common set of target genes enriched in regulating cell cycle and proliferation to support the Ras-dependency. Furthermore, correlated with the strength of Ras signaling as indicated by the ELK1 phosphorylation level, MED23 was up-regulated by Ras-transformation, and was found to be overexpressed in both Ras-mutated lung cancer cell lines and primary tumor samples. Remarkably, lower Med23 expression predicts better survival in Ras-active lung cancer patients and xenograft mice. Collectively, our findings demonstrate a critical role for MED23 in enabling the 'Ras-addiction' of lung carcinogenesis, thus providing a vulnerable target for the treatment of Ras-active lung cancer. To gain a genome-wide understanding of how MED23 and ELK1 control gene expression in Ras-active lung cancer cells, we performed gene profiling experiments to analyze the transcriptomes from control, si-Med23, or si-Elk1 A549 cells. The si-Ctrl, si-Med23 and si-Elk1 A549 cells were cultured in the normal condition. Then the cells were harvested for RNA extraction and hybridization on Affymetrix microarrays. The analysis contain 9 samples. si-Ctrl cells have three replicates (si-Ctrl#1, si-Ctrl#2 and si-Ctrl#3), and the si-Med23 or si-Elk1 group contains three different cell lines that harbor three different RNAi oligos against Med23 or Elk1 (si-Med23A, B, C and si-Elk1A, B, C).
2013-08-31 | E-GEOD-40517 | biostudies-arrayexpress
Project description:In response to myeloablative stresses, HSCs are rapidly activated to replenish myeloid progenitors, while maintaining full potential of self-renewal to ensure life-long hematopoiesis. However, the key factors that orchestrate HSC activities during physiological stresses remain largely unknown. Here we report that Med23 controls the myeloid potential of activated HSCs. Ablation of Med23 in hematopoietic system leads to lymphocytopenia. Med23- deficient HSCs undergo myeloid-biased differentiation and lose the self-renewal capacity. Interestingly, Med23-deficient HSCs are much easier to be activated in response to physio- logical stresses. Mechanistically, Med23 plays essential roles in maintaining stemness genes expression and suppressing myeloid lineage genes expression. Med23 is downregulated in HSCs and Med23 deletion results in better survival under myeloablative stress. Altogether, our findings identify Med23 as a gatekeeper of myeloid potential of HSCs, thus providing unique insights into the relationship among Med23-mediated transcriptional regulations, the myeloid potential of HSCs and HSC activation upon stresses.
2018-07-14 | GSE112008 | GEO
Project description:Liver fibrosis, often associated with cirrhosis and hepatocellular carcinomas, is characterized by hepatic damage, an inflammatory response, and hepatic stellate cell (HSC) activation, although the underlying mechanisms are largely unknown.Here,we show that the MED23 subunit of the transcriptional Mediator complex participates in the development of experimental liver fibrosis. Compared with their control littermates, mice with hepatic Med23 deletion exhibited aggravated CCl4-induced liver fibrosis, with enhanced chemokine production and inflammatory infiltration as well as increased hepatocyte regeneration. Mechanistically, the orphan nuclear receptor RORα activates the expression of the liver fibrosis-related chemokines CCL5 and CXCL10, which is suppressed by the Mediator subunit MED23. We further found that the inhibition of Ccl5 and Cxcl10 expression by MED23 likely occurs due to G9a-mediated H3K9 dimethylation of the target promoters. Collectively, these findings reveal hepatic MED23 as a key modulator of chemokine production and inflammatory responses and define the MED23-CCL5/CXCL10 axis as a potential target for clinical intervention in liver fibrosis.
2020-06-06 | GSE137457 | GEO
Project description:K-RAS activating mutations occur frequently in non-small cell lung cancer (NSCLC), leading to aberrant activation of Ras-MAPK signaling pathway that contributes to the malignant phenotype. However, the development of Ras-targeted therapeutics remains challenging. Here, we show that MED23, a component of the multisubunit Mediator complex that is known to integrate signaling and gene activities, is selectively important for Ras-active lung cancer. By screening a large panel of human lung cancer cell lines with or without a Ras mutation, we found that Med23 RNAi specifically inhibits the proliferation and tumorigenicity of lung cancer cells with hyperactive Ras activity. Med23-deficiency in fibroblasts selectively inhibited the oncogenic transformation induced by Ras but not by c-Myc. Transcription factor ELK1, which is phosphorylated by MAPK for relaying the Ras signaling to MED23, was also required for the Ras-driven oncogenesis. Transcriptiome analysis revealed that MED23 and ELK1 co-regulate a common set of target genes enriched in regulating cell cycle and proliferation to support the Ras-dependency. Furthermore, correlated with the strength of Ras signaling as indicated by the ELK1 phosphorylation level, MED23 was up-regulated by Ras-transformation, and was found to be overexpressed in both Ras-mutated lung cancer cell lines and primary tumor samples. Remarkably, lower Med23 expression predicts better survival in Ras-active lung cancer patients and xenograft mice. Collectively, our findings demonstrate a critical role for MED23 in enabling the “Ras-addiction” of lung carcinogenesis, thus providing a vulnerable target for the treatment of Ras-active lung cancer. To gain a genome-wide understanding of how MED23 and ELK1 control gene expression in Ras-active lung cancer cells, we performed gene profiling experiments to analyze the transcriptomes from control, si-Med23, or si-Elk1 A549 cells.
2013-08-31 | GSE40517 | GEO
Project description:Mediator complex function as an integrative hub for transcriptional regulation. Here we show that Mediator subunit MED23 regulate glucose and lipid metabolism via FOXO1 in liver. Here, we have generated a liver-specific Med23-knockout (LMKO) mouse and found that Med23-deletion in liver improved glucose and lipid metabolism, as well as insulin responsiveness, and prevented diet-induced obesity. Mechanistically, MED23 participated in gluconeogenesis and cholesterol synthesis by interacting with FOXO1. Disruption of this interaction by hepatic Med23-deletion impaired the Mediator and RNAP II recruitment and partially reduced the expression of the FOXO1 target genes. Remarkably, acute hepatic Med23 knockdown in db/db mice significantly improved insulin sensitivity. Overall, our data revealed Mediator MED23 as a critical regulator of glucose and lipid metabolism, suggesting novel therapeutic strategies against metabolic diseases.
2015-03-16 | GSE48966 | GEO
Project description:Mediator complex is an integrative hub for transcriptional regulation. Here we show that Mediator regulates alternative mRNA processing via its Med23 subunit. Combining tandem affinity purification and mass spectrometry, we identified a number of mRNA processing factors that bind to a soluble recombinant Mediator subunit MED23 but not to several other Mediator components. One of these factors, hnRNP L, specifically interacts with MED23 in vitro and in vivo. Consistently, Mediator partially colocalizes with hnRNP L and the splicing machinery in the cell. Functionally Med23 regulates a subset of hnRNP L-targeted alternative splicing (AS) and alternative cleavage and polyadenylation (APA) events as shown by minigene reporters and exon array analysis. ChIP-seq analysis revealed that Med23 can regulate hnRNP L occupancy at their co-regulated genes. Taken together, these results demonstrate a crosstalk between Mediator and the splicing machinery, suggesting a novel mechanism for coupling mRNA processing to transcription. We performed an exon array experiment using HeLa cells expressing Med23, hnRNP L or control siRNAs which were established by a virus-mediated siRNA technology. Each sample was done in three biological replicates. Total RNA of these cell lines was processed and hybridized to the Affymetrix human exon array.
2012-02-24 | E-GEOD-33771 | biostudies-arrayexpress