Significant role for p16INK4a in p53-independent telomere-directed senescence.
Telomere attrition in primary human fibroblasts induces replicative senescence accompanied by activation of the p53 and p16(INK4a)/RB tumor suppressor pathways. Although the contribution of p53 and its target, p21, to telomere-driven senescence have been well established, the role of p16(INK4a) is controversial. Attempts to dissect the significance of p16(INK4a) in response to telomere shortening have been hampered by the concomitant induction of p16(INK4a) by cell culture conditions. To circumvent this problem, we studied the role of p16(INK4a) in the cellular response to acute telomere damage induced by a dominant negative allele of TRF2, TRF2(Delta B Delta M). This approach avoids the confounding aspects of culture stress because parallel cultures with and without telomere damage can be compared. Telomere damage generated with TRF2(Delta B Delta M) resulted in induction of p16(INK4a) in the majority of cells as detected by immunohistochemistry. Inhibition of p16(INK4a) 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 p16(INK4a) and p53 led to nearly complete bypass of telomere-directed senescence. We conclude that p16(INK4a) contributes to the p53-independent response to telomere damage.
Jacobs
Jacqueline J L
JJ
Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10021 USA.
de Lange
Titia
T
D001973:Bromodeoxyuridine; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D016615:Telomere / Q000502:physiology*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
D019941:Cyclin-Dependent Kinase Inhibitor p16; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; D001973:Bromodeoxyuridine