This Article Full Text Full Text (PDF) Supplemental material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hammond, E. M. Articles by Giaccia, A. J. Search for Related Content PubMed PubMed Citation Articles by Hammond, E. M. Articles by Giaccia, A. J.

Genome-Wide Analysis of p53 under Hypoxic Conditions

Division of Radiation and Cancer Biology, Department of Radiation Oncology,¹ Department of Genetics, Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, California 94303-5152²

Received 28 June 2005/ Returned for modification 15 September 2005/ Accepted 2 February 2006

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.

Supplemental material for this article may be found at http://mcb.asm.org.

This article has been cited by other articles:

• Roy, S., Jeffrey, R., Tenniswood, M. (2008). Array-based analysis of the effects of trichostatin A and CG-1521 on cell cycle and cell death in LNCaP prostate cancer cells. Molecular Cancer Therapeutics 7: 1931-1939 [Abstract] [Full Text]  
• Johnson, T. M., Meade, K., Pathak, N., Marques, M. R., Attardi, L. D. (2008). Knockin mice expressing a chimeric p53 protein reveal mechanistic differences in how p53 triggers apoptosis and senescence. Proc. Natl. Acad. Sci. USA 105: 1215-1220 [Abstract] [Full Text]  
• Stiehl, D. P., Fath, D. M., Liang, D., Jiang, Y., Sang, N. (2007). Histone Deacetylase Inhibitors Synergize p300 Autoacetylation that Regulates Its Transactivation Activity and Complex Formation. Cancer Res. 67: 2256-2264 [Abstract] [Full Text]  
• Roy, S., Tenniswood, M. (2007). Site-specific Acetylation of p53 Directs Selective Transcription Complex Assembly. J. Biol. Chem. 282: 4765-4771 [Abstract] [Full Text]  
• Mattia, M., Gottifredi, V., McKinney, K., Prives, C. (2007). p53-Dependent p21 mRNA Elongation Is Impaired when DNA Replication Is Stalled. Mol. Cell. Biol. 27: 1309-1320 [Abstract] [Full Text]  
• Krieg, A. J., Hammond, E. M., Giaccia, A. J. (2006). Functional Analysis of p53 Binding under Differential Stresses.. Mol. Cell. Biol. 26: 7030-7045 [Abstract] [Full Text]