Current Biology
Volume 14, Issue 24, 29 December 2004, Pages 2302-2308
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Significant Role for p16INK4a in p53-Independent Telomere-Directed Senescence

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Abstract

Telomere attrition in primary human fibroblasts induces replicative senescence accompanied by activation of the p53 and p16INK4a/RB tumor suppressor pathways. Although the contribution of p53 and its target, p21, to telomere-driven senescence have been well established, the role of p16INK4a is controversial. Attempts to dissect the significance of p16INK4a in response to telomere shortening have been hampered by the concomitant induction of p16INK4a by cell culture conditions. To circumvent this problem, we studied the role of p16INK4a in the cellular response to acute telomere damage induced by a dominant negative allele of TRF2, TRF2ΔBΔM. This approach avoids the confounding aspects of culture stress because parallel cultures with and without telomere damage can be compared. Telomere damage generated with TRF2ΔBΔM resulted in induction of p16INK4a in the majority of cells as detected by immunohistochemistry. Inhibition of p16INK4a with shRNA or overexpression of BMI1 had a significant effect on the telomere damage response in p53-deficient cells. While p53 deficiency alone only partially abrogated the telomere damage-induced cell cycle arrest, combined inhibition of p16INK4a and p53 led to nearly complete bypass of telomere-directed senescence. We conclude that p16INK4a contributes to the p53-independent response to telomere damage.

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Present address: Department of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.