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Mutant p53 cooperates with ETS2 to promote etoposide resistance.

ABSTRACT: Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5'-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53-expressing cells to etoposide and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially "druggable" component of mtp53's gain-of-function activity.

SUBMITTER: Do PM

PROVIDER: S-EPMC3337457 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Mutant p53 cooperates with ETS2 to promote etoposide resistance.

Do Phi M PM Varanasi Lakshman L Fan Songqing S Li Chunyang C Kubacka Iwona I Newman Virginia V Chauhan Krishna K Daniels Silvano Rakeem SR Boccetta Maurizio M Garrett Michael R MR Li Runzhao R Martinez Luis A LA

Genes & development 20120401 8

Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5'-tyrosyl DNA phosphodiest ...[more]

PMID: 22508727

Similar Datasets

Mutant p53 cooperates with ETS2 to promote etoposide resistance

Project description:This SuperSeries is composed of the following subset Series: GSE36749: Mutant p53 cooperates with ETS2 to promote etoposide resistance [ChIP-Seq] GSE36751: Mutant p53 cooperates with ETS2 to promote etoposide resistance [ChIP-chip] Refer to individual Series

2012-05-02 | E-GEOD-36752 | biostudies-arrayexpress

Mutant p53 cooperates with ETS2 to promote etoposide resistance

Project description:This SuperSeries is composed of the SubSeries listed below.

2012-05-03 | GSE36752 | GEO

Mutant p53 cooperates with ETS2 to promote etoposide resistance [ChIP-Seq]

Project description:Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms including disabling pro-apoptotic proteins and by regulating gene expression. Analysis of promoter regions identified through CHIP-on-CHIP and CHIP-SEQ platforms reveal that the ETS motif (EBS) is prevalent within predicted mtp53 binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters, and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5’-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53 expressing cells to etoposide, and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially “druggable” component of mtp53’s gain-of-function activity. Comparison of two different transcriptional binding analysis (ChIP-on-ChIP and ChIP-Seq) for the identification of novel mutant p53 binding.

2012-05-02 | E-GEOD-36749 | biostudies-arrayexpress

Mutant p53 cooperates with ETS2 to promote etoposide resistance [ChIP-chip]

2012-05-02 | E-GEOD-36751 | biostudies-arrayexpress

Mutant p53 cooperates with ETS2 to promote etoposide resistance [ChIP-chip]

2012-05-03 | GSE36751 | GEO

Mutant p53 cooperates with ETS2 to promote etoposide resistance [ChIP-Seq]

2012-05-03 | GSE36749 | GEO

Mutant p53 protects ETS2 from non-canonical COP1/DET1 dependent degradation.

Project description:Mutations in the tumor suppressor gene TP53 contribute to the development of approximately half of all human cancers. One mechanism by which mutant p53 (mtp53) acts is through interaction with other transcription factors, which can either enhance or repress the transcription of their target genes. Mtp53 preferentially interacts with the erythroblastosis virus E26 oncogene homologue 2 (ETS2), an ETS transcription factor, and increases its protein stability. To study the mechanism underlying ETS2 degradation, we knocked down ubiquitin ligases known to interact with ETS2. We observed that knockdown of the constitutive photomorphogenesis protein 1 (COP1) and its binding partner De-etiolated 1 (DET1) significantly increased ETS2 stability, and conversely, their ectopic expression led to increased ETS2 ubiquitination and degradation. Surprisingly, we observed that DET1 binds to ETS2 independently of COP1, and we demonstrated that mutation of multiple sites required for ETS2 degradation abrogated the interaction between DET1 and ETS2. Furthermore, we demonstrate that mtp53 prevents the COP1/DET1 complex from ubiquitinating ETS2 and thereby marking it for destruction. Mechanistically, we show that mtp53 destabilizes DET1 and also disrupts the DET1/ETS2 complex thereby preventing ETS2 degradation. Our study reveals a hitherto unknown function in which DET1 mediates the interaction with the substrates of its cognate ubiquitin ligase complex and provides an explanation for the ability of mtp53 to protect ETS2.

| S-EPMC4914304 | biostudies-literature

Integrative genome analysis of somatic p53 mutant osteosarcomas identifies Ets2-dependent regulation of small nucleolar RNAs by mutant p53 protein.

Project description:TP53 is the most frequently mutated gene in human cancer. Many mutant p53 proteins exert oncogenic gain-of-function (GOF) properties that contribute to metastasis, but the mechanisms mediating these functions remain poorly defined in vivo. To elucidate how mutant p53 GOF drives metastasis, we developed a traceable somatic osteosarcoma mouse model that is initiated with either a single p53 mutation (p53R172H) or p53 loss in osteoblasts. Our study confirmed that p53 mutant mice developed osteosarcomas with increased metastasis as compared with p53-null mice. Comprehensive transcriptome RNA sequencing (RNA-seq) analysis of 16 tumors identified a cluster of small nucleolar RNAs (snoRNAs) that are highly up-regulated in p53 mutant tumors. Regulatory element analysis of these deregulated snoRNA genes identified strong enrichment of a common Ets2 transcription factor-binding site. Homozygous deletion of Ets2 in p53 mutant mice resulted in strong down-regulation of snoRNAs and reversed the prometastatic phenotype of mutant p53 but had no effect on osteosarcoma development, which remained 100% penetrant. In summary, our studies identify Ets2 inhibition as a potential therapeutic vulnerability in p53 mutant osteosarcomas.

| S-EPMC5695086 | biostudies-literature

Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis.

Project description:ASXL1 mutations occur frequently in myeloid neoplasms and are associated with poor prognosis. However, the mechanisms by which mutant ASXL1 induces leukaemogenesis remain unclear. In this study, we report mutually reinforcing effects between a C-terminally truncated form of mutant ASXL1 (ASXL1-MT) and BAP1 in promoting myeloid leukaemogenesis. BAP1 expression results in increased monoubiquitination of ASXL1-MT, which in turn increases the catalytic function of BAP1. This hyperactive ASXL1-MT/BAP1 complex promotes aberrant myeloid differentiation of haematopoietic progenitor cells and accelerates RUNX1-ETO-driven leukaemogenesis. Mechanistically, this complex induces upregulation of posterior HOXA genes and IRF8 through removal of H2AK119 ubiquitination. Importantly, BAP1 depletion inhibits posterior HOXA gene expression and leukaemogenicity of ASXL1-MT-expressing myeloid leukemia cells. Furthermore, BAP1 is also required for the growth of MLL-fusion leukemia cells with posterior HOXA gene dysregulation. These data indicate that BAP1, which has long been considered a tumor suppressor, in fact plays tumor-promoting roles in myeloid neoplasms.

| S-EPMC6048047 | biostudies-literature

Prolactin cooperates with loss of p53 to promote claudin-low mammary carcinomas.

Project description:TP53 is one of the most commonly mutated genes in cancer. In breast cancer, it is mutated in about 40% of primary clinical tumors and is associated with poor survival. The mammotrophic hormone, prolactin (PRL), and/or its receptor are also expressed in many breast cancers, and accumulating epidemiologic data link PRL to breast cancer development and progression. Like TP53 mutations, evidence for PRL activity is evident across several molecular cancer subtypes, and elevated PRL expression and loss of p53 have been observed in some of the same clinical tumors. In order to examine the interaction of these factors, we used genetically modified mouse models of mammary-specific p53 loss and local overexpression of PRL. We demonstrated that mammary PRL decreased the latency of tumors in the absence of p53, and increased the proportion of triple-negative claudin-low carcinomas, which display similarities to human clinical metaplastic carcinomas. Moreover, PRL/p53(-/-) carcinomas displayed higher rates of proliferation and more aggressive behavior. Transcripts associated with cell cycle progression, invasion and stromal reactivity were differentially expressed in carcinomas that developed in the presence of elevated PRL. PRL/p53(-/-) carcinomas also exhibited selectively altered expression of activating protein-1 components, including higher levels of c-Jun and FosL1, which can drive transcription of many of these genes and the epithelial-mesenchymal transition. The ability of PRL to promote claudin-low carcinomas demonstrates that PRL can influence this subset of triple-negative breast cancers, which may have been obscured by the relative infrequency of this cancer subtype. Our findings suggest novel therapeutic approaches, and provide a preclinical model to develop possible agents.

| S-EPMC4007359 | biostudies-literature

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