PUMA inactivation protects against oxidative stress through p21/Bcl-XL inhibition of bax death.
The tumor suppressor protein p53 activates growth arrest and proapoptotic genes in response to DNA damage. It is known that negative feedback by p21(Cip1/Waf1/Sdi1) represses p53-dependent transactivation of PUMA. The current study investigates PUMA feedback on p53 during oxidative stress from hyperoxia and the subsequent effects on cell survival mediated through p21 and Bcl-X(L). Deletion of PUMA in HCT116 colon carcinoma cells increased levels of p53 and p21, resulting in a larger G(1) population during hyperoxia. P21-dependent increase in Bcl-X(L) levels protected PUMA-deficient cells against hyperoxic cell death. Bax and Bak were both able to promote hyperoxic cell death. Bcl-X(L) protection against hyperoxic death was lost in cells lacking Bax, not PUMA, suggesting that Bcl-X(L) acts to inhibit Bax-dependent death. These results indicate that PUMA exerts a negative feedback on p53 and p21, leading to p21-dependent growth suppressive and survival changes. Enhanced survival was associated with increased Bcl-X(L) to block Bax activated cell death during oxidative stress.
Vitiello
Peter F
PF
Department of Environmental Medicine, School of Medicine and Dentistry, The University of Rochester, Rochester NY 14642, USA.
Staversky
Rhonda J
RJ
Keng
Peter C
PC
O'Reilly
Michael A
MA
D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors*; D017353:Gene Deletion; D006801:Humans; D018384:Oxidative Stress; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein