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Molecular and Cellular Biology, June 2006, p. 4161-4171, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.02142-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Prohibitin Facilitates Cellular Senescence by Recruiting Specific Corepressors To Inhibit E2F Target Genes

Shipra Rastogi, Bharat Joshi ,{dagger},{ddagger} Piyali Dasgupta,{ddagger} Mark Morris, Kenneth Wright, and Srikumar Chellappan*

Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Dr., Tampa, Florida 33612

Received 4 November 2005/ Returned for modification 14 December 2005/ Accepted 20 March 2006

Prohibitin is a growth regulatory gene that has pleiotropic functions in the nucleus, mitochondria, and cytoplasmic compartments. Earlier studies had proposed a role for prohibitin in modulating cellular senescence, but the underlying mechanisms remain unknown. Here we show that senescence induced by DNA-damaging agents causes the localization of prohibitin to specific heterochromatic foci. Prohibitin could bind to heterochromatin protein 1 (HP1) family proteins and colocalized with HP1{gamma} in senescence-associated heterochromatic foci. Further, HP1{gamma} could synergize with prohibitin to repress E2F1-mediated transcriptional activity. The depletion of prohibitin by small interfering RNA or antisense techniques led to a reduction in the senescent phenotype, correlating with a reduced expression of senescence-associated ß-galactosidase and fewer numbers of senescence-associated heterochromatic foci. Chromatin immunoprecipitation assays showed that prohibitin is needed for the recruitment of HP1{gamma} to E2F1-regulated proliferative promoters, leading to their repression. The ablation of prohibitin prevented the recruitment of HPI{gamma}, but not Suv39H, to the promoters upon senescence. Prohibitin-mediated recruitment of HP1{gamma} occurred in only senescent cells, not in quiescent cells; thus, there is a dichotomy in the recruitment of different corepressors by prohibitin, depending on the type of growth arrest. These studies show that prohibitin plays a vital role in inducing cellular senescence.

* Corresponding author. Mailing address: Dept. of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Dr., Tampa, FL 33612. Phone: (813) 745-6892. Fax: (813) 745-6748. E-mail: Chellasp{at}moffitt.usf.edu.

{dagger} Present address: Department of Cellular and Physiological Sciences, University of British Columbia, 2177 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, June 2006, p. 4161-4171, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.02142-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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