The p53 transcriptional response across tumor types reveals core and senescence-specific signatures modulated by long noncoding RNAs
| Autor: | Jordan Bendor, Jesse R. Zamudio, Nadya Dimitrova, Elena Martínez-Terroba, Christiane E. Olivero, David M. Feldser, Lauren Winkler, Kevin Chen, Ephrath Tesfaye |
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| Rok vydání: | 2021 |
| Předmět: |
p53
senescence Carcinogenesis Mice 0302 clinical medicine lncRNA Neoplasms 2.1 Biological and endogenous factors Cellular Senescence Cancer 0303 health sciences Multidisciplinary Tumor Biological Sciences Chromatin PVT1 Cell biology Gene Expression Regulation Neoplastic 5.1 Pharmaceuticals 030220 oncology & carcinogenesis RNA Long Noncoding Long Noncoding tumor suppression transcription Signal Transduction Senescence Pediatric Research Initiative Physiological Biology Stress Cell Line Proto-Oncogene Proteins c-myc 03 medical and health sciences Mediator Stress Physiological Cell Line Tumor Genetics Animals E2F Gene Psychological repression 030304 developmental biology Cell Proliferation Neoplastic E2F Transcription Factors Gene Expression Regulation Tumor progression RNA Tumor Suppressor Protein p53 DNA Damage Genome-Wide Association Study |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 118, iss 31 Proceedings of the National Academy of Sciences of the United States of America |
| Popis: | Significance The work by Tesfaye and colleagues defines universal and tumor type–specific features of the p53 tumor suppressor transcriptional network. This study determines a “core” signature of the p53 response across different oncogenic contexts, which defines a universal set of p53 target genes. In addition, this study clarifies the basis for outcome specificity downstream of p53 activation in different oncogenic contexts. We observe that while apoptosis in lymphoma cells is not primarily determined by p53’s transcriptional activity, p53 indirectly promotes senescence in lung adenocarcinoma and sarcoma cells by activating the cis-regulatory long noncoding RNA Pvt1b, which represses Myc levels and its proliferative function. The p53 pathway is a universal tumor suppressor mechanism that limits tumor progression by triggering apoptosis or permanent cell cycle arrest, called senescence. In recent years, efforts to reactivate p53 function in cancer have proven to be a successful therapeutic strategy in murine models and have gained traction with the development of a range of small molecules targeting mutant p53. However, knowledge of the downstream mediators of p53 reactivation in different oncogenic contexts has been limited. Here, we utilized a panel of murine cancer cell lines from three distinct tumor types susceptible to alternative outcomes following p53 restoration to define unique and shared p53 transcriptional signatures. While we found that the majority of p53-bound sites and p53-responsive transcripts are tumor-type specific, analysis of shared targets identified a core signature of genes activated by p53 across all contexts. Furthermore, we identified repression of E2F and Myc target genes as a key feature of senescence. Characterization of p53-induced transcripts revealed core and senescence-specific long noncoding RNAs (lncRNAs) that are predominantly chromatin associated and whose production is coupled to cis-regulatory activities. Functional investigation of the contributions of p53-induced lncRNAs to p53-dependent outcomes highlighted Pvt1b, the p53-dependent isoform of Pvt1, as a mediator of p53-dependent senescence via Myc repression. Inhibition of Pvt1b led to decreased activation of senescence markers and increased levels of markers of proliferation. These findings shed light on the core and outcome-specific p53 restoration signatures across different oncogenic contexts and underscore the key role of the p53-Pvt1b-Myc regulatory axis in mediating proliferative arrest. |
| Databáze: | OpenAIRE |
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