p21 in cancer: intricate networks and multiple activities

Abstract

One of the main engines that drives cellular transformation is the loss of proper control of the mammalian cell cycle. The cyclin-dependent kinase inhibitor p21 (also known as p21 WAF1/Cip1 ) promotes cell cycle arrest in response to many stimuli. It is well positioned to function as both a sensor and an effector of multiple anti-proliferative signals. This Review focuses on recent advances in our understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.Higher eukaryotes have evolved multiple checkpoint mechanisms to monitor and respond to cellular perturbations, halting cellular progression until errors are fixed or the environment becomes permissible to the faithful transmission of genetic material 1 . Perturbations in checkpoint mechanisms are detrimental to the integrity of the genome, promote cancer development 2 and significantly affect the efficacy of anticancer treatment 3 . The tumour suppressor protein p53 mediates the DNA damage-induced checkpoint through the transactivation of various growth inhibitory or apoptotic genes. Among these, the small 165 amino acid protein p21 (also known as p21 WAF1/Cip1 ) mediates p53-dependent G1 growth arrest 4,5 . Earlier studies supported the view that p21 suppresses tumours by promoting cell cycle arrest in response to various stimuli. Additionally, substantial evidence from biochemical and genetic studies indicates that p21 acts as a master effector of multiple tumour suppressor pathways for promoting anti-proliferative activities that are independent of the classical p53 tumour suppressor pathway (FIG. 1). Despite its profound role in halting cellular proliferation and its ability to promote differentiation and cellular senescence, recent studies suggest that, under certain conditions, p21 can promote cellular proliferation and oncogenicity 6 . Consequently, p21 is often misregulated in human cancers, but its expression, depending on the cellular context and circumstances, suggests that it can act as a tumour suppressor or as an oncogene (TABLE 1). p21 mediates its various biological activities primarily by binding to and inhibiting the kinase activity of the cyclin-dependent kinases (CDKs) CDK2 and CDK1 (also known as CDC2) leading to growth arrest at specific stages in the cell cycle (FIG. 2). In addition, by binding to proliferating cell nuclear antigen (PCNA), p21 interferes with PCNA-dependent DNA NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript polymerase activity, thereby inhibiting DNA replication and modulating various PCNAdependent DNA repair processes. In this Review we discuss recent advances concerning the complex role of p21 in the development of cancer. We describe the various effector functions of p21 that allow it to exert its biological activities. We further describe our current understanding of the various mechanisms that control p21 expression, both transcri...

p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation

“…However, the proposed p21 functions outside the cell cycle are poorly defined and somewhat controversial. A number of studies have presented evidence that p21 can protect cells from apoptosis induced by genotoxic insults or chemotherapeutics both in vitro and in animal models (Gartel and Tyner, 2002;Abbas and Dutta, 2009). Most of these studies have used DNA damage to activate p53 that is known to induce both p53-dependent and p53-independent signaling events, making the data difficult to interpret and sometimes confusing.…”

“…In addition to its cell-cycle inhibitor function, p21 has been reported to affect either negatively or positively another major p53 function, induction of apoptosis (Abbas and Dutta, 2009). In response to DNA damage and subsequent p53 activation, cells can either undergo cell-cycle arrest or apoptosis depending on the extend of damage and other still unknown factors (Vousden and Lu, 2002).…”

An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis

“…In addition, the inhibition of histone deacetylases (HDACs) has been known to selectively induce p21 (Johnstone, 2002;Dokmanovic et al, 2007), although the impact of acetylation on p21 turnover remains uncertain. Precise control of p21 abundance is required for its role in cellcycle regulation, thus further elucidating the regulatory mechanism of p21 stabilization is an important priority toward a greater understanding of p21 deregulation in human cancer (Abbas and Dutta, 2009).…”

Effects on apoptosis and cell cycle arrest contribute to the antitumor responses of interleukin-27 mediated by retrovirus in human pancreatic carcinoma cells

“…Earlier studies supported the view that p21 suppresses tumors by promoting cell cycle arrest in response to various stimuli (25). Additionally, substantial evidence from biochemical and genetic studies indicates that p21 acts as a master effector of multiple tumor suppressor pathways for promoting independent anti-proliferative activities (26). Survivin normally functions as an essential factor for chromosome segregation and cytokinesis during cell division (27).…”