Phenotype Specific Analyses Reveal Distinct Regulatory Mechanism for Chronically Activated p53

Kristina Kirschner, Shamith A. Samarajiwa, Jonathan M. Cairns, Suraj Menon, Pedro A. Pérez-Mancera, Kosuke Tomimatsu, Camino Bermejo-Rodriguez, Yoko Ito, Tamir Chandra, Masako Narita, Scott K. Lyons, Andy G. Lynch, Hiroshi Kimura, Tetsuya Ohbayashi, Simon Tavaré, Masashi Narita

研究成果: Contribution to journalArticle査読

28 被引用数 (Scopus)

抄録

The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage) and chronically activated (in senescent or pro-apoptotic conditions) p53. Compared to the classical ‘acute’ p53 binding profile, ‘chronic’ p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory ‘p53 hubs’ where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the ‘lipogenic phenotype’, a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms.

本文言語英語
論文番号e1005053
ジャーナルPLoS genetics
11
3
DOI
出版ステータス出版済み - 3 19 2015
外部発表はい

All Science Journal Classification (ASJC) codes

  • 生態、進化、行動および分類学
  • 分子生物学
  • 遺伝学
  • 遺伝学(臨床)
  • 癌研究

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