Phenotype Specific Analyses Reveal Distinct Regulatory Mechanism for Chronically Activated p53

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The p53 transcription factor is a frequently mutated tumour suppressor that contributes to repairing or eliminating damaged cells. Levels of p53 are typically regulated through its stability; it is constantly produced and degraded, so that upon stress, p53 is up-regulated quickly. This acutely induced p53 has been used as a major model system for studying genome-wide p53 targets. However, emerging evidence suggests that persistently activated p53 is involved in cancer-associated phenotypes, such as cellular senescence. We investigate genome-wide gene regulation by acutely induced p53 through DNA damage as well as chronically activated p53 in oncogene-induced senescence and pro-apoptotic states. Interestingly, acute and chronic p53 DNA binding profiles are highly distinctive, the latter being preferentially associated with larger and relatively open promoters called CpG islands. Furthermore, our integrative analyses of both p53-dependent gene expression and p53-binding genomic DNA profiles reveal that p53 and many of its targets in chronic conditions form extensive self-regulatory hubs, where they can physically interact. The data not only substantially extend the list of direct p53 targets but highlight unique gene regulation by chronic p53. Finally we show that the cancer-associated lipogenic enzyme, stearoyl-CoA desaturase, is a bona fide p53-repressive target through its CpG island promoter in chronic conditions.

Vyšlo v časopise: Phenotype Specific Analyses Reveal Distinct Regulatory Mechanism for Chronically Activated p53. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005053
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005053

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