This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jackson, J. G. Articles by Pereira-Smith, O. M. Search for Related Content PubMed PubMed Citation Articles by Jackson, J. G. Articles by Pereira-Smith, O. M.

p53 Is Preferentially Recruited to the Promoters of Growth Arrest Genes p21 and GADD45 during Replicative Senescence of Normal Human Fibroblasts

University of Texas Health Science Center at San Antonio, Department of Cellular and Structural Biology, Sam and Ann Barshop Institute for Longevity and Aging Studies, San Antonio, Texas

Requests for reprints: James G. Jackson, Department of Cellular and Structural Biology, Sam and Ann Barshop Institute for Longevity and Aging Studies, STCBM Building, 15355 Lambda Drive, San Antonio, TX 78245-3207. Phone: 210-562-5075; Fax: 210-562-5093; E-mail: jacksonjg{at}uthscsa.edu.

Replicative senescence is the terminal growth arrest that most normal human cells enter into after a fixed number of divisions in vitro, limiting the proliferative potential of a cell and preventing genomic instability caused by critically short telomeres. Thus, senescence presents a tumor-suppressive mechanism and a barrier to tumor formation. However, senescent cells are inherently resistant to apoptosis and, as they accumulate in aging tissues, may contribute to organ dysfunction and promote tumor progression as part of the stromal environment. Replicative life span in normal human cells can be extended by inactivation of the tumor suppressor gene p53 or its direct target, the cyclin-dependent kinase inhibitor p21, suggesting a direct role for this pathway in senescence. However, p53 recruitment to promoters of target genes during replicative senescence has not been shown in live cells. In this study, we used chromatin immunoprecipitation to determine that p53 preferentially occupied the promoters of growth arrest genes p21 and GADD45 in senescent normal human diploid fibroblasts but not the promoters of other target genes that recruited p53 following doxorubicin-induced DNA damage, such as apoptosis regulators TNFRSF10b, TNFRSF6, and PUMA. This differential recruitment of p53 in senescent versus doxorubicin-treated fibroblasts was accompanied by differences in post-translational modification of p53. These data provide mechanisms for both the growth arrest mediated by p53 and the resistant nature of senescent cells to apoptosis despite p53 activity. (Cancer Res 2006; 66(17): 8356-60)

This article has been cited by other articles:

				L. L. Song, F. Alimirah, R. Panchanathan, H. Xin, and D. Choubey Expression of an IFN-Inducible Cellular Senescence Gene, IFI16, Is Up-Regulated by p53 Mol. Cancer Res., November 1, 2008; 6(11): 1732 - 1741. [Abstract] [Full Text] [PDF]

				R. Mudhasani, Z. Zhu, G. Hutvagner, C. M. Eischen, S. Lyle, L. L. Hall, J. B. Lawrence, A. N. Imbalzano, and S. N. Jones Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells J. Cell Biol., October 22, 2008; 181(7): 1055 - 1063. [Abstract] [Full Text] [PDF]

				R. S. M. Shih, S. H. K. Wong, N. W. Schoene, and K. Y. Lei Suppression of Gadd45 Alleviates the G2/M Blockage and the Enhanced Phosphorylation of p53 and p38 in Zinc Supplemented Normal Human Bronchial Epithelial Cells Experimental Biology and Medicine, March 1, 2008; 233(3): 317 - 327. [Abstract] [Full Text] [PDF]

				A. Marusyk, L. J. Wheeler, C. K. Mathews, and J. DeGregori p53 Mediates Senescence-Like Arrest Induced by Chronic Replicational Stress Mol. Cell. Biol., August 1, 2007; 27(15): 5336 - 5351. [Abstract] [Full Text] [PDF]

				S. S. A. Coates, B. E. Lehnert, S. Sharma, S. M. Kindell, and R. K. Gary Beryllium Induces Premature Senescence in Human Fibroblasts J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 70 - 79. [Abstract] [Full Text] [PDF]