Homo sapiens
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PROVIDER: PRJNA137055 | ENA |
REPOSITORIES: ENA
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Project description:The proto-oncogenes ETV1, ETV4, and ETV5 encode members of the E26 transformation-specific (ETS) transcription factor family, which includes the most frequently rearranged and overexpressed genes in prostate cancer. Despite being critical regulators of development, little is known about their post-translational regulation. Here we identify the ubiquitin ligase COnstitutive Photomorphogenic-1 (COP1, also called RFWD2) as a tumor suppressor that negatively regulates ETV1, ETV4, and ETV5. ETV1, which is the member mutated more frequently in prostate cancer, was degraded after being ubiquitinated by COP1. Truncated ETV1 encoded by prostate cancer translocation TMPRSS2:ETV1 lacks the critical COP1 binding motifs (degrons) and was 50-fold more stable than wild-type ETV1. Almost all patient translocations eliminate these ETV1 degrons, implying that translocations rendering ETV1 insensitive to COP1 confer a significant selective advantage to prostate epithelial cells. Indeed, COP1 deficiency in mouse prostate elevated ETV1 levels and produced increased cell proliferation, hyperplasia, and early prostate intraepithelial neoplasia. The combined loss of COP1 and PTEN enhanced the invasiveness of mouse prostate adenocarcinomas. Finally, relatively rare human prostate cancer samples showed hemizygous loss of the COP1 gene, loss of COP1 protein expression, and abnormally elevated ETV1 protein while lacking a translocation event. These findings identify COP1 as a bona fide tumor suppressor whose down-regulation promotes prostatic epithelial cell proliferation and tumorigenesis. LNCap prostate cancer cell line were treated with 5 different sets of siRNAs: (1) control siRNA; (2) COP1 (RFWD2) siRNA; (3) COP1 siRNA + ETV1 siRNA; (4) COP1 siRNA + c-JUN siRNA; (5) COP1 siRNA + ETV1 siRNA + c-JUN siRNA. The experiments were conducted in two batches; each batch has its own control siRNA group, so that the batch effect can be properly modelled. Each group has 4-6 replicates; there are 31 samples in total.
2011-04-08 | E-GEOD-27914 | biostudies-arrayexpress
Project description:The proto-oncogenes ETV1, ETV4, and ETV5 encode members of the E26 transformation-specific (ETS) transcription factor family, which includes the most frequently rearranged and overexpressed genes in prostate cancer. Despite being critical regulators of development, little is known about their post-translational regulation. Here we identify the ubiquitin ligase COnstitutive Photomorphogenic-1 (COP1, also called RFWD2) as a tumor suppressor that negatively regulates ETV1, ETV4, and ETV5. ETV1, which is the member mutated more frequently in prostate cancer, was degraded after being ubiquitinated by COP1. Truncated ETV1 encoded by prostate cancer translocation TMPRSS2:ETV1 lacks the critical COP1 binding motifs (degrons) and was 50-fold more stable than wild-type ETV1. Almost all patient translocations eliminate these ETV1 degrons, implying that translocations rendering ETV1 insensitive to COP1 confer a significant selective advantage to prostate epithelial cells. Indeed, COP1 deficiency in mouse prostate elevated ETV1 levels and produced increased cell proliferation, hyperplasia, and early prostate intraepithelial neoplasia. The combined loss of COP1 and PTEN enhanced the invasiveness of mouse prostate adenocarcinomas. Finally, relatively rare human prostate cancer samples showed hemizygous loss of the COP1 gene, loss of COP1 protein expression, and abnormally elevated ETV1 protein while lacking a translocation event. These findings identify COP1 as a bona fide tumor suppressor whose down-regulation promotes prostatic epithelial cell proliferation and tumorigenesis.
2011-04-08 | GSE27914 | GEO
Project description:In order to assess the physiological role of Cop1 in vivo we generated mice that do no longer express the protein. Cop1KO mice die at around E10.5 of embryonic development. In order to gain insights into the molecular mechanisms that cause the embryonic death we compared the genome-wide gene expression profile of E9.5 wild-tytpe and Cop1-null embryos. The data do not support a role for Cop1 in the regulation of the p53 pathway in vivo and highlight a role for Cop1 in cardiovascular development and/or angiogenesis. The abstract of the associated publication is as follows:Biochemical data have suggested conflicting roles for the E3 ubiquitin ligase Cop1 in tumourigenesis. Here we present the first in vivo investigation of the role of Cop1 in cancer aetiology. We used an innovative genetic approach to generate an allelic series of Cop1 and show that Cop1 hypomorphic mice spontaneously develop malignancy at a high frequency in their first year of life and are highly susceptible to radiation-induced lymphomagenesis. Biochemically, we show that Cop1 regulates c-Jun oncoprotein stability and modulates c-Jun/AP1 transcriptional activity in vivo. Cop1-deficiency stimulates cell proliferation in a c-Jun-dependent manner. We conclude that Cop1 is a tumour suppressor that antagonizes c-Jun oncogenic activity in vivo. RNA from 6 different control embryos (+/+ or +/-) were mixed and subdivided into control pool 1 and pool 2. RNA from 6 different Cop-null embryos were mixed and subdivided into KO pool 1 and pool 2.
2011-01-13 | E-GEOD-18636 | biostudies-arrayexpress
Project description:Identification of BRD32048 as an inhibitor of ETV1 oncogenic transcription factor. This compound was indentified by small molecule mcroarray (a binding assay). It was able to consistently inhibit an ETV1-dependent MMP1-driven luciferase signal. Its direct binding was validated by Suface plasmon resonance (Biacore assay). It inhibits ETV1-driven invasion in ETV1-dependent cell lines. The goal of this gene expression comparison was to interogate the effects of BRD32048 on the global gene expression and to define the degree to which its siganture overlaps with an ETV1-specific shRNA-induced gene expression signature. The gene expression analysis was performed for two ETV1- dependent cell lines. (a) LNCaP (prostate cancer) uses a DOX-inducible system where two different ETV1sh (sh1117 and sh872) are induced for 4 days. In parallel cells were treated with 20 M-BM-5M BRD32048 for 16 hours. The control was DMSO treated cells. (b) SK-MEL-28 were infected with two different ETV1sh (sh3 and sh5) and selected in puromycin for 4 days. The sh control used was GFPsh. In parallel cells were treated with 20 M-BM-5M BRD32048 for 16 hours. The control was DMSO treated cells. Total RNA was isolated and measured with expression arrays. The data was normalized (see data processing) and the gene expression signatures (fold change >1.5 in either direction) were interested bteween the experimental conditions for each cell line.
2013-11-07 | E-GEOD-52154 | biostudies-arrayexpress
Project description:In order to assess the physiological role of Cop1 in vivo we generated mice that do no longer express the protein. Cop1KO mice die at around E10.5 of embryonic development. In order to gain insights into the molecular mechanisms that cause the embryonic death we compared the genome-wide gene expression profile of E9.5 wild-tytpe and Cop1-null embryos. The data do not support a role for Cop1 in the regulation of the p53 pathway in vivo and highlight a role for Cop1 in cardiovascular development and/or angiogenesis. The abstract of the associated publication is as follows:Biochemical data have suggested conflicting roles for the E3 ubiquitin ligase Cop1 in tumourigenesis. Here we present the first in vivo investigation of the role of Cop1 in cancer aetiology. We used an innovative genetic approach to generate an allelic series of Cop1 and show that Cop1 hypomorphic mice spontaneously develop malignancy at a high frequency in their first year of life and are highly susceptible to radiation-induced lymphomagenesis. Biochemically, we show that Cop1 regulates c-Jun oncoprotein stability and modulates c-Jun/AP1 transcriptional activity in vivo. Cop1-deficiency stimulates cell proliferation in a c-Jun-dependent manner. We conclude that Cop1 is a tumour suppressor that antagonizes c-Jun oncogenic activity in vivo.
2011-01-13 | GSE18636 | GEO
Project description:Aberrant activation of the mitogen-activated protein kinase (MAPK) cascade promotes oncogenic transcriptomes. Despite efforts to inhibit oncogenic kinases, such as BRAFV600E, tumor responses in patients can be heterogeneous and limited by drug resistance mechanisms. Here, we describe patient tumors that acquired COP1 or DET1 mutations after treatment with the BRAFV600E inhibi-tor vemurafenib. COP1 and DET1 constitute the substrate adaptor of the E3 ubiquitin ligase CRL4COP1/DET1, which targets transcription factors, including ETV1, ETV4, and ETV5, for pro-teasomal degradation. MAPK-MEK-ERK signaling prevents CRL4COP1/DET1 from ubiquitinating ETV1, ETV4, and ETV5, but the mechanistic details are still being elucidated. We found that pa-tient mutations in COP1 or DET1 inactivated CRL4COP1/DET1 in melanoma cells, stabilized ETV1, ETV4, and ETV5, and conferred resistance to inhibitors of the MAPK pathway. ETV5, in partic-ular, enhanced cell survival and was found to promote the expression of the pro-survival gene BCL2A1. Indeed, the deletion of pro-survival BCL2A1 re-sensitized COP1 mutant cells to vemu-rafenib treatment. These observations indicate that the post-translational regulation of ETV5 by CRL4COP1/DET1 modulates transcriptional outputs in ERK-dependent cancers, and its inactivation contributes to therapeutic resistance.
2025-06-24 | GSE203467 | GEO
Project description:Aberrant activation of the mitogen-activated protein kinase (MAPK) cascade promotes oncogenic transcriptomes. Despite efforts to inhibit oncogenic kinases, such as BRAFV600E, tumor responses in patients can be heterogeneous and limited by drug resistance mechanisms. Here, we describe patient tumors that acquired COP1 or DET1 mutations after treatment with the BRAFV600E inhibi-tor vemurafenib. COP1 and DET1 constitute the substrate adaptor of the E3 ubiquitin ligase CRL4COP1/DET1, which targets transcription factors, including ETV1, ETV4, and ETV5, for pro-teasomal degradation. MAPK-MEK-ERK signaling prevents CRL4COP1/DET1 from ubiquitinating ETV1, ETV4, and ETV5, but the mechanistic details are still being elucidated. We found that pa-tient mutations in COP1 or DET1 inactivated CRL4COP1/DET1 in melanoma cells, stabilized ETV1, ETV4, and ETV5, and conferred resistance to inhibitors of the MAPK pathway. ETV5, in partic-ular, enhanced cell survival and was found to promote the expression of the pro-survival gene BCL2A1. Indeed, the deletion of pro-survival BCL2A1 re-sensitized COP1 mutant cells to vemu-rafenib treatment. These observations indicate that the post-translational regulation of ETV5 by CRL4COP1/DET1 modulates transcriptional outputs in ERK-dependent cancers, and its inactivation contributes to therapeutic resistance.
2025-06-24 | GSE203469 | GEO
Project description:Aberrant activation of the mitogen-activated protein kinase (MAPK) cascade promotes oncogenic transcriptomes. Despite efforts to inhibit oncogenic kinases, such as BRAFV600E, tumor responses in patients can be heterogeneous and limited by drug resistance mechanisms. Here, we describe patient tumors that acquired COP1 or DET1 mutations after treatment with the BRAFV600E inhibi-tor vemurafenib. COP1 and DET1 constitute the substrate adaptor of the E3 ubiquitin ligase CRL4COP1/DET1, which targets transcription factors, including ETV1, ETV4, and ETV5, for pro-teasomal degradation. MAPK-MEK-ERK signaling prevents CRL4COP1/DET1 from ubiquitinating ETV1, ETV4, and ETV5, but the mechanistic details are still being elucidated. We found that pa-tient mutations in COP1 or DET1 inactivated CRL4COP1/DET1 in melanoma cells, stabilized ETV1, ETV4, and ETV5, and conferred resistance to inhibitors of the MAPK pathway. ETV5, in partic-ular, enhanced cell survival and was found to promote the expression of the pro-survival gene BCL2A1. Indeed, the deletion of pro-survival BCL2A1 re-sensitized COP1 mutant cells to vemu-rafenib treatment. These observations indicate that the post-translational regulation of ETV5 by CRL4COP1/DET1 modulates transcriptional outputs in ERK-dependent cancers, and its inactivation contributes to therapeutic resistance
2025-06-24 | GSE203468 | GEO
Project description:Chromosomal rearrangements involving ETS factors, ERG and ETV1, occur frequently in prostate cancer. We here examine human prostate cancer cells control VCaP and LNCaP cells with ERG- or ETV1-silenced VCaP or LNCaP cells, respectively, in hormone deprived and stimulated conditions.
2013-03-01 | GSE39354 | GEO