p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation.
p21(Waf1/Cip1) is a p53 transcription target implicated in both major functions of the tumor suppressor--cell cycle arrest and apoptosis. It is a potent inhibitor of the key cyclin-dependent kinases (CDK1-4), and has been thought to be the main mediator of p53-dependent G1 and G2 arrest. However, an increasing body of information suggests that in addition to its cell-cycle inhibitory activity, p21 can affect p53-dependent apoptosis. These data have been obtained from experiments in which p53 is activated primarily by genotoxic stress. In this study, we use the selective MDM2 antagonist, nutlin-3a, as a nongenotoxic p53 activator and show that the cell-cycle arrest function of p21 is dependent on the cellular context. In most cancer cell lines, p53-dependent p21 induction is essential for cell-cycle arrest, but in some, p21 is dispensable. Depletion of p21 did not increase the apoptotic response to nutlin-3a in all seven cancer cell lines tested and p21 overexpression did not protect apoptosis-sensitive lines from death. p21 was found to mediate nutlin-induced p53-dependent downregulation of another antiapoptotic protein, survivin, without significantly affecting the apoptotic outcome. Taken together our results suggest that p21 induction does not affect the apoptotic response to nongenotoxic p53 activation.
Xia
M
M
Discovery Oncology, Roche Research Center, Hoffmann-La Roche Inc, Nutley, NJ 07110, USA.
Knezevic
D
D
Vassilev
L T
LT
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology*; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D010879:Piperazines; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D004317:Doxorubicin