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 p21Cip1/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-XL. Deletion of PUMA in HCT116 colon carcinoma cells increased levels of p53 and p21, resulting in a larger G1 population during hyperoxia. P21-dependent increase in Bcl-XL levels protected PUMA-deficient cells against hyperoxic cell death. Bax and Bak were both able to promote hyperoxic cell death. Bcl-XL protection against hyperoxic death was lost in cells lacking Bax, not PUMA, suggesting that Bcl-XL 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-XL to block Bax activated cell death during oxidative stress.