title: Down-regulation of p21WAF1 promotes apoptosis in senescent human fibroblasts: involvement of retinoblastoma protein phosphorylation and delay of cellular aging.
abstract: It has been suggested that genes which exercise checkpoint control during cell cycle traverse are equally important to the process of apoptotic cell death. In this study, we show that the key cell cycle regulatory gene p21(WAF1) is also involved in the execution of apoptosis. p21(WAF1) expression was down-regulated during NaBu-induced apoptosis of senescent normal diploid human 2BS fibroblasts. Conversely, when p21(WAF1) expression was actively suppressed in 2BS cells by a stably transfected antisense p21(WAF1) construct, apoptosis was accelerated and senescence was delayed, as shown by several markers of cell aging. Down-regulation of p21(WAF1) by antisense caused an increase in the phosphorylation and inactivation of pRb. Phosphorylation of pRb was further enhanced upon induction of apoptosis by NaBu. Our results suggest that p21(WAF1), acting through the phosphorylation of pRb, regulates whether 2BS cells cease to proliferate and become senescent but resistant to apoptosis, or whether they accelerate proliferation while becoming more susceptible to apoptotic stimuli.
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University, Health Science Center, Beijing 100083, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Corbley
authors.forename: Zuoqin
authors.initials: Z
authors.lastname: Tang
authors.forename: Long
authors.initials: L
authors.lastname: Yang
authors.forename: Yong
authors.initials: Y
authors.lastname: Peng
authors.forename: Zong Yu
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Tan Jun
authors.initials: TJ
authors.lastname: Tong
mesh_terms: D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D016615:Telomere / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D016160:Retinoblastoma Protein