Pivotal Role of the Cyclin-dependent Kinase Inhibitor p21WAF1/CIP1 in Apoptosis and Autophagy

Abstract

Programmed cell death (PCD) is involved in a variety of biologic events. Based on the morphologic appearance of the cells, there are two types of PCD as follows: apoptotic (type I) and autophagic (type II). However, the molecular machinery that determines the type of PCD is poorly defined. The purpose of this study was to show whether the presence of the cyclin-dependent kinase (CDK) inhibitor p21, a modulator of apoptosis, determines which type of PCD the cell undergoes. Treatment with C 2 -ceramide was associated with both the cleavage of caspase-3 and poly(ADP-ribose) polymerase and the degradation of autophagy-related Beclin 1 and Atg5 proteins, without a change in the cyclin-CDK activity, which culminated in apoptosis in p21 ؉/؉ mouse embryonic fibroblasts (MEFs). On the other hand, C 2 -ceramide did not cleave caspase-3 or poly(ADP-ribose) polymerase and kept Beclin 1 and Atg5 proteins stable in p21 ؊/؊ MEFs, events that this time culminated in autophagy. When expression of the p21 protein was inhibited by small interfering RNA or when the overexpression of Beclin 1 or Atg5 was induced, autophagy rather than apoptosis was initiated in the p21 ؉/؉ MEFs treated with C 2 -ceramide. In contrast, the exogenous expression of p21 or the silencing of Beclin 1 and Atg5 with small interfering RNA increased the number of apoptotic cells and decreased the number of autophagic cells among C 2 -ceramidetreated p21 ؊/؊ MEFs. ␥-Irradiation, which endogenously generates ceramide, induced a similar tendency in these MEFs. These results suggest that p21 plays an essential role in determining the type of cell death, positively for apoptosis and negatively for autophagy.

Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells

“…2 and 4). As p53 downstream target p21 functions as a suppressor of apoptosis and autophagy (17,18), p21 suppression may be a critical factor to induce dual programmed cell death pathways in response p53 overexpression. Suppression of p21 expression by genetic deletion or artificial p21 target microRNA has been shown to enhance the Ad-p53-induced apoptosis (18,35).…”

“…Dual cell death pathways, such as apoptosis and autophagy, induced by p53 transactivation are mainly involved in the suppression of tumor initiation and progression. However, among the p53 downstream target genes, p21, which is most rapidly and strongly induced during the DNA damage response, mainly induces cell-cycle arrest through suppression of apoptotic and autophagic cell death pathways (17,18). Thus, p21 suppression may be a more effective strategy for the induction of apoptotic and autophagic cell death pathways in tumor cells, particularly when the tumor suppressor p53 gene is overexpressed in tumor cells in response to cancer gene therapy.…”

The autophagic paradox in cancer therapy

“…As opposed to p27, the role of another CDK inhibitor p21 is more equivocal. Although p21 has been shown to impair C(2)-ceramide-and CD40-induced autophagic activity, enforced expression of cytoplasmic p21 induces autophagy (Fujiwara et al, 2008;Portillo et al, 2010;. These findings indicate that, similar to p53, the regulatory effect of p21 on autophagy may depend on its subcellular localization.…”

Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma

“…30 A recent study indicates that p21 acts as a mediator of the apoptotic pathway and a negative regulator of autophagy. 31 We previously showed that statins increased p21 expression through inhibition of HDAC activity. 32 Furthermore, statins were found to induce p21-dependent autophagy.…”