Genome-wide analysis of p53 under hypoxic conditions

Ester M. Hammond, Daniel J. Mandell, Ali Salim, Adam J. Krieg, Thomas M. Johnson, Haider A. Shirazi, Laura D. Attardi, Amato J. Giaccia

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Hypoxia is an important nongenotoxic stress that modulates the tumor suppressor activity of p53 during malignant progression. In this study, we investigated how genotoxic and nongenotoxic stresses regulate p53 association with chromatin, p53 transcriptional activity, and p53-dependent apoptosis. We found that genotoxic and nongenotoxic stresses result in the accumulation and binding of the p53 tumor suppressor protein to the same cognate binding sites in chromatin. However, it is the stress that determines whether downstream signaling is mediated by association with transcriptional coactivators. In contrast to p53 induced by DNA-damaging agents, hypoxia-induced p53 has primarily transrepression activity. Using extensive microarray analysis, we identified families of repressed targets of p53 that are involved in cell signaling, DNA repair, cell cycle control, and differentiation. Following our previous study on the contribution of residues 25 and 26 to p53-dependent hypoxia-induced apoptosis, we found that residues 25-26 and 53-54 and the polyproline- and DNA-binding regions are also required for both gene repression and the induction of apoptosis by p53 during hypoxia. This study defines a new role for residues 53 and 54 of p53 in regulating transrepression and demonstrates that 25-26 and 53-54 work in the same pathway to induce apoptosis through gene repression.

Original languageEnglish (US)
Pages (from-to)3492-3504
Number of pages13
JournalMolecular and cellular biology
Volume26
Issue number9
DOIs
StatePublished - May 1 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Genome-wide analysis of p53 under hypoxic conditions'. Together they form a unique fingerprint.

  • Cite this

    Hammond, E. M., Mandell, D. J., Salim, A., Krieg, A. J., Johnson, T. M., Shirazi, H. A., Attardi, L. D., & Giaccia, A. J. (2006). Genome-wide analysis of p53 under hypoxic conditions. Molecular and cellular biology, 26(9), 3492-3504. https://doi.org/10.1128/MCB.26.9.3492-3504.2006