Mutant p53 rescues human diploid cells from senescence without inhibiting the induction of SDI1/WAF1.
Although the cyclin-dependent kinase inhibitor p21SDI1 (WAF1/CIP1) has been proposed as the mediator of p53-induced cell cycle arrest following DNA damage, several stimuli now appear to induce SDI1 independent of p53 function. We have examined the behavior of p53 and SDI1 in an isogeneic model by manipulating p53 status in normal diploid human fibroblasts using an amphotropic retroviral vector. Following DNA strand break damage induced by bleomycin, both SDI1 induction and G1-S cell cycle arrest are p53 dependent, consistent with SDI1 being the key mediator. In contrast, in cellular senescence (and following UV irradiation), induction of SDI1 occurs independent of p53 function yet growth arrest is still p53 dependent. We conclude (a) that redundant pathways exist for induction of SDI1, but that (b) SDI1, while perhaps necessary, is not sufficient for inhibition of cell cycle progression, requiring the cooperation of an additional factor (possibly another cyclin-dependent kinase inhibitor) whose expression, at least in the case of senescence, is strictly p53 dependent.
Bond
J A
JA
Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom.
Blaydes
J P
JP
Rowson
J
J
Haughton
M F
MF
Smith
J R
JR
Wynford-Thomas
D
D
Wyllie
F S
FS
D001761:Bleomycin / Q000633:toxicity; D002455:Cell Division / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D004249:DNA Damage; D004171:Diploidy; D015536:Down-Regulation / Q000528:radiation effects; D016193:G1 Phase / Q000502:physiology; D005786:Gene Expression Regulation / Q000528:radiation effects; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D016196:S Phase / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D014466:Ultraviolet Rays
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D001761:Bleomycin