EGFR is a target of the tumor suppressor E3-ligase FBXW7
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ABSTRACT:
PROVIDER: PRJNA1035070 | ENA |
REPOSITORIES: ENA
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Project description:FBXW7 is and E3 ubiquitin ligase and is highly mutated in colorectal cancer. We used human colon organoids with engineered FBXW7 hotspot mutations to investigate novel targets of E3 ligase activity with a combined transcriptomic and proteomic approach uncovering the EGFR-MAPK pathway as highly regulated by the E3 ligase activity.
2024-04-03 | GSE246896 | GEO
Project description:We assessed the role of the E3 ligase FBXW7 in mature B-cell neoplasms. This experiment assesses the role of the FBXW7-KMT2D axis in regulating gene expression in OPM-1 cells.
2020-04-07 | GSE148131 | GEO
Project description:The Hace1 E3 ligase is a tumor suppressor in stressed cells. Through unknown mechanisms, Hace1 indirectly targets the cyclin D1 proto-oncogene for proteasomal degradation during nutrient depletion. We now show that Hace1 targets HIF1alpha for VHL-dependent degradation during hypoxia. To better understand these diverse actions we performed mass spectrometry to identify Hace1-interacting proteins. We show that Hace1 interacts with cullin-associated NEDD8-dissociated protein 1 (CAND1) under nutrient depletion and hypoxia. CAND1 binds cullins and prevents their entry into cullin ring E3 ligase (CRL) complexes, thus blocking CRL activity. Hace1 binding releases CUL1/2 from CAND1, facilitating assembly of CRL complexes to degrade cyclin D1 and HIF1alpha, respectively. These findings suggest a broad role for Hace1 in regulating tumor suppressive CRL E3 ligases. In this study, we used gene expression profiling to characterize how Hace1 overexpression affect the transcriptional response to hypoxic stress Using Affymetrix exon-level microarrays, we compared the expression profile of HEK293 cells overexpressing either Hace1 or MSCV vector alone, under hypoxia or normoxia
2011-07-01 | E-GEOD-25452 | biostudies-arrayexpress
Project description:The Hace1 E3 ligase is a tumor suppressor in stressed cells. Through unknown mechanisms, Hace1 indirectly targets the cyclin D1 proto-oncogene for proteasomal degradation during nutrient depletion. We now show that Hace1 targets HIF1alpha for VHL-dependent degradation during hypoxia. To better understand these diverse actions we performed mass spectrometry to identify Hace1-interacting proteins. We show that Hace1 interacts with cullin-associated NEDD8-dissociated protein 1 (CAND1) under nutrient depletion and hypoxia. CAND1 binds cullins and prevents their entry into cullin ring E3 ligase (CRL) complexes, thus blocking CRL activity. Hace1 binding releases CUL1/2 from CAND1, facilitating assembly of CRL complexes to degrade cyclin D1 and HIF1alpha, respectively. These findings suggest a broad role for Hace1 in regulating tumor suppressive CRL E3 ligases. In this study, we used gene expression profiling to characterize how Hace1 overexpression affect the transcriptional response to hypoxic stress
2011-07-01 | GSE25452 | GEO
Project description:It has been recognized that BRCA1, in the form of the BRCA1/BARD1 heterodimer, acting as an ubiquitin E3 ligase offered a possible mechanism to explain its pleiotrophic nature of BRCA1 activity. Our observation that mice lacking BRCA1 enzymatic activity are viable apart from male sterility was unexpected. Our results suggest that the E3 ligase activity of BRCA1 is largely dispensable for normal development and is not essential for all BRCA1 functions. Thus, many of the known and unknown functions of BRCA1 are likely to be mediated independent of its ability to catalyze ubiquitination. The genome copy number patterns were studied on the mice tumors that lacks E3 ubiqitin ligase activity of BRCA1 and were compared to copy number profile of mice lacking p53 and both brca1 and p53. Array CGH was performed using Agilent mouse CGH microarray 244K kit. Genomic DNA isolated from tumor tissue and its corresponding mouse tail were labelled with two different dyes and hybridized simultaneously on to microarray slides to perform comparitive genomic hybridization.
2011-08-25 | E-GEOD-31673 | biostudies-arrayexpress
Project description:The budding yeast E3 SUMO ligase Mms21, a component of the Smc5-6 complex, regulates sister chromatid cohesion, DNA replication, and DNA repair. We identify a role for Mms21 in ribosome biogenesis. The mms21RINGD mutant exhibits reduced rRNA production, nuclear accumulation of 60S and 40S ribosomal proteins, and elevated Gcn4 translation. Genes involved in ribosome biogenesis and translation are down-regulated in the mms21RINGD mutant. Examining gene expression profile of mms21RINGD mutant compared to wild-type by RNA Seq using Ilumina sequencing
2015-06-13 | E-GEOD-69826 | biostudies-arrayexpress
Project description:Current models imply that the FERM domain protein Merlin, encoded by the tumor suppressor NF2, inhibits mitogenic signaling at or near the plasma membrane. Here, we show that the closed, growth inhibitory form of Merlin accumulates in the nucleus, binds to the E3 ubiquitin ligase CRL4DCAF1, and suppresses its activity. Depletion of DCAF1 blocks the promitogenic effect of inactivation of Merlin. Conversely, enforced expression of a Merlin-insensitive mutant of DCAF1 counteracts the antimitogenic effect of Merlin. Re-expression of Merlin and silencing of DCAF1 induce a similar, tumor-suppressive program of gene expression. Tumor-derived mutations invariably disrupt Merlinâs ability to interact with or inhibit CRL4DCAF1. Finally, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. We propose that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4DCAF1. To examine if Merlin controls gene expression through inhibition of CRL4DCAF1, and define the general function of this ligase, we compared the gene expression program activated by expression of Merlin or by depletion of DCAF1 in Merlin-null FC-1801 mouse Schwannoma cells
2010-03-09 | E-GEOD-19305 | biostudies-arrayexpress
Project description:It has been recognized that BRCA1, in the form of the BRCA1/BARD1 heterodimer, acting as an ubiquitin E3 ligase offered a possible mechanism to explain its pleiotrophic nature of BRCA1 activity. Our observation that mice lacking BRCA1 enzymatic activity are viable apart from male sterility was unexpected. Our results suggest that the E3 ligase activity of BRCA1 is largely dispensable for normal development and is not essential for all BRCA1 functions. Thus, many of the known and unknown functions of BRCA1 are likely to be mediated independent of its ability to catalyze ubiquitination. The genome copy number patterns were studied on the mice tumors that lacks E3 ubiqitin ligase activity of BRCA1 and were compared to copy number profile of mice lacking p53 and both brca1 and p53.
2011-08-26 | GSE31673 | GEO
Project description:Background: TP53, the most frequently mutated gene in human cancers, orchestrates a complex transcriptional program crucial for cancer prevention. While certain TP53-dependent genes have been extensively studied, others, like the recently identified RNF144B, remained poorly understood. This E3 ubiquitin ligase has shown potent tumor suppressor activity in murine Eμ Myc-driven lymphoma, emphasizing its significance in the TP53 network. However, little is known about its targets and its role in cancer development, requiring further exploration. In this work, we investigate RNF144B's impact on tumor suppression beyond the hematopoietic compartment in human cancers. Methods: Employing TP53 wild-type cells, we generated models lacking RNF144B in both non-transformed and cancerous cells of human and mouse origin. By using proteomics, transcriptomics, and functional analysis, we assessed RNF144B's impact in cellular proliferation and transformation. Through In vitro and in vivo experiments, we explored proliferation, transformation potential, DNA repair, cell cycle control, mitotic progression, and treatment resistance. Findings were contrasted with clinical datasets and bioinformatics analysis. Results: Our research underscores RNF144B's pivotal role as a tumor suppressor, particularly in lung adenocarcinoma. In both human and mouse oncogene-expressing cells, RNF144B deficiency heightened cellular proliferation and transformation. Proteomic and transcriptomic analysis revealed RNF144B's novel function in mediating protein degradation associated with cell cycle progression, DNA damage response and genomic stability. RNF144B deficiency induced chromosomal instability, mitotic defects, and correlated with elevated aneuploidy and worse prognosis in human tumors. Furthermore, RNF144B-deficient lung adenocarcinoma cells exhibited resistance to cell cycle inhibitors that induce chromosomal instability. Conclusions: PRJNA1092607Supported by clinical data, our study suggests that RNF144B plays a pivotal role in maintaining genomic stability during tumor suppression.
2024-04-02 | GSE262951 | GEO
Project description:RNF12 is a developmental E3 ligase mutated in Tonne-Kalscheuer Syndrome patients. To identify the gene expression programme controlled by RNF12 activity in mouse embryonic stem cells we employ RNA-Sequencing.
2020-04-29 | GSE149554 | GEO