Prohibitin facilitates cellular senescence by recruiting specific corepressors to inhibit E2F target genes.
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 HP1gamma in senescence-associated heterochromatic foci. Further, HP1gamma 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 beta-galactosidase and fewer numbers of senescence-associated heterochromatic foci. Chromatin immunoprecipitation assays showed that prohibitin is needed for the recruitment of HP1gamma to E2F1-regulated proliferative promoters, leading to their repression. The ablation of prohibitin prevented the recruitment of HPIgamma, but not Suv39H, to the promoters upon senescence. Prohibitin-mediated recruitment of HP1gamma 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.
Rastogi
Shipra
S
Dept. of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Dr., Tampa, FL 33612, USA.
Joshi
Bharat
B
Dasgupta
Piyali
P
Morris
Mark
M
Wright
Kenneth
K
Chellappan
Srikumar
S
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics*; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D050684:E2F Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006570:Heterochromatin / Q000235:genetics; D006801:Humans; D000091402:Prohibitins; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D001616:beta-Galactosidase / Q000378:metabolism
D002868:Chromosomal Proteins, Non-Histone; D050684:E2F Transcription Factors; D006570:Heterochromatin; D000091402:Prohibitins; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5; D001616:beta-Galactosidase