Differential regulation of p21 by p53 and Rb in cellular response to oxidative stress

Abstract

Oxidative stress to mammalian cells causes cellular damage and triggers inducible cellular responses leading to cell death by apoptosis. In this paper, we report that p53 was required for programmed cell death induced by oxidative stress in both mouse and human cells and that p53 transactivation was involved in induction of oxidative cell death. Furthermore, we show that p21 was highly responsive to oxidative stress in a p53-dependent manner and that ectopic expression of p21 could increase cellular susceptibility to oxidative stress in the absence of p53. However, p21 was not required for p53-directed oxidative cell death because mouse embryo fibroblasts MEFs lacking p21(p21-/- MEFs) were still susceptible to oxidative cell death. Interestingly, bax, a cell-death mediator regulated by p53, was overexpressed in p21-/- MEFs that underwent cell death by oxidative stress, suggesting a compensation for loss of p21 that may be responsible for the existence of cell-death responses in p21-knockout mouse fibroblasts. Finally, we provide evidence that the retinoblastoma gene product (Rb) is a negative regulator of p21 and a repressor of the cellular apoptotic process. Because p21 is regulated by p53 positively and by Rb negatively, p21 may be a link between p53 and Rb in determining cell fate after oxidative damage.

DUSP1 Is Controlled by p53 during the Cellular Response to Oxidative Stress

“…For example, g radiation causes cell cycle arrest in mouse embryo fibroblasts (MEF) in a p53-dependent manner (20), whereas oxidative stress induces cell death by apoptosis in the same type of mouse cells and that also depends on p53 (21). Similarly, we have observed that normal human fibroblasts undergo G 1 arrest in response to radiation-induced DNA damage, but cell death after oxidative stress was induced by H 2 O 2 (22). The molecular basis for differential regulation of cell cycle arrest versus cell death by p53 is not known.…”

PAC1 is a direct transcription target of E2F-1 in apoptotic signaling

“…Therefore, identification of important components involved in the cellular response to oxidative stress may reveal targets for chemotherapeutic strategies. We have previously demonstrated that p53 is essential for the cellular apoptotic response to oxidative stress (Yin et al, 1998(Yin et al, , 1999. We further identified two MAP kinase inhibitors, PAC1 and MKP-2, as downstream targets of p53 function in apoptosis signaling (Yin et al, 2003;Shen et al, 2006).…”

Nrf2 and p21 regulate the fine balance between life and death by controlling ROS levels

“…8 Furthermore, cellular stress that does not damage DNA, such as hypoxia or exposure to ribonucleotide biosynthesis inhibitors, may also induce p53-dependent expression of p21. 7 In our recent study, 9 we have revealed a novel mechanism by which p21 protects cells against oxidative stress through upregulation of the Nrf2 signaling pathway.…”