Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage

doi:10.1016/j.dnarep.2016.04.008

DNA Repair

Volume 42, June 2016, Pages 63-71

https://doi.org/10.1016/j.dnarep.2016.04.008 Get rights and content

Abstract

An appropriate control over cell cycle progression depends on many factors. Cyclin-dependent kinase (CDK) inhibitor p21 (also known as p21^WAF1/Cip1) is one of these factors that promote cell cycle arrest in response to a variety of stimuli. The inhibitory effect of P21 on cell cycle progression correlates with its nuclear localization. P21 can be induced by both p53-dependent and p53-independent mechanisms. Some other important functions attributed to p21 include transcriptional regulation, modulation or inhibition of apoptosis. These functions are largely dependent on direct p21/protein interactions and also on p21 subcellular localizations. In addition, p21 can play a role in DNA repair by interacting with proliferating cell nuclear antigen (PCNA). In this review, we will focus on the multiple functions of p21 in cell cycle regulation, apoptosis and gene transcription after DNA damage and briefly discuss the pathways and factors that have critical roles in p21 expression and activity.

Introduction

The CDK inhibitor p21, also known as p21waf1^/cip1 or P21/CDKN1A [1], is a small protein with 165 amino acids and belongs to the CIP/Kip family of CDKs inhibitors [2]. P21 is a well-known inhibitor of cell cycle and can arrest the cell cycle progression in G1/S and G2/M transitions by inhibiting CDK4,6/cyclin-D and CDK2/cyclin-E, respectively. It is believed that the regulation of cell growth by p21 is mediated by control of E2F activity [3], [4]. Progression of the mammalian cell cycle is regulated by CDKs and regulatory subunits cyclins, cell cycle progression is triggered by partial phosphorylation of Rb by CDK-Cyclin, and P21 disrupts this interactions and inhibit cell cycle progression[5]. p21 gene was the first to be identified to be induced by wild-type p53 protein [6]. The arrest of cell cycle in G1/S transition is a p53-dependent process caused by factors such as taxol, transforming growth factor beta (TGFβ) or oncogenic Ras, and can be associated with cyclin E and cyclin A/CDK genes. p21 gene expression can be induced by growth factors such as TGFβ or mimosine in a p53-independent manner [7], [8], [9]. Despite its ability in inhibition of cell cycle, p21 can protect cells against apoptosis. This ability relies to a large extent, on the gene transcriptional regulation through protein–protein interaction or DNA repair activity of p21. For instance, cytoplasmic p21 can bind to proteins involved in induction of apoptosis and inhibit the activity of such proteins [1]. It has also been shown that the activity of p21 on CDKs is stoichiometry related, such that it may inhibit or stimulate CDK4/6 complexes depending on its abundance [9]. PCNA is yet another factor that is inhibited by interacting with carboxy-terminal of p21 [10]. It is also worth mentioning that p21 is a co-activator of DNA polymerase δ [9]. p21 is potentially capable to preclude PCNA interaction with factors like pol δ [11] results in suppression of DNA polymerase δ activation [12] and inhibits DNA replication [13].

Section snippets

Regulation of p21

p53 is the main transcriptional regulator of p21. p21 contains two conserved p53 responsive elements (p53RE) in its promoter. The two p53 homologues including p63 and p73 can transactivate p21 through binding to p53RE. Various stresses including DNA damage and oxidative stress upregulate p53 activity and subsequently result in p21 expression [14]. p53 phosphorylation on multiple serine/threonine residues increases the transcriptional activity of p53 by enhancing p53 stability. Prolyl-isomerase

p21 and cell cycle

Cell cycle is a process underlying duplication of cells. Transitions of cell cycle from G₁ to S and G₂ to mitosis is regulated by sequential activation and inactivation of CDK family of proteins, a family of serine/threonine protein kinases. Cyclin is the regulatory subunit of CDK and is degraded or synthesized during cell cycle. Of the many (more than 21) identified CDKs so far, only CDK1, CDK2, CDK4 and CDK6 are required for cell cycle regulation [19], [20]. All cyclins share a similar region

p21 and apoptosis

Several studies have shown that p21 has a key function in carcinogenesis and promotion of tumors. Inhibition of apoptosis is the best-known oncogenic function of p21. This is evidenced by the fact that p21 knockdown by radiation decreases tumorigenesis [11]. Several studies have shown that p21 protects numerous cell types from apoptosis; for instance, the overexpression of p21 in cell lines of breast cancer has been reported to decrease cell sensitivity to infrared (IR)-induced apoptosis. Plus,

Cytoplasmic p21

Akt can be activated by various stimulants such as insulin and several growth factors. Phosphatidylinositol 3-phosphate kinase (PI3K) activates Akt by phosphorylating Ser-473 and Thr-308 residues. Phosphorylation of Akt results in activation of various substrates such as BAD and caspase as well as forkhead family transcription factors that down-regulate apoptosis and enhance survival. In Akt-mediated survival pathway, p21 has been phosphorylated on two residues including Thr-145(phosphorylated

The relationship between p21 and p53R2

p53R2, is a p53-inducible protein that has a p53-binding site on intron 1. A 351-amino acid peptide is encoded by p53R2 related gene and is highly similar to R2 subunit of ribonucleotide reductase (RR) [86]. The produced dNTPs are incorporated into two major processes: (1) DNA synthesis by RR in S-phase and (2) DNA damage repair by p53R2 during cell cycle arrest in G1 or G2 phase [87]. Following DNA damage which is associated with increase in p53 levels, the p53R2 expression also increases [88]

Correlation of p21 with PI3K/Akt/p21

Akt regulates many cellular processes including cell growth, survival/apoptosis, angiogenesis, metabolism and protein synthesis [96], [97], [98]. Akt controls several down-stream signaling pathway for example transcription factors such as NF-κB, fork head/AFX, CREB and p53, apoptosis machinery proteins such as BAD and caspase 9, cell cycle regulators such as p21, p27, mTOR and cyclinD1, and finally factors involved in metabolism such as GSK-3 [99]. Several studies have noted the overexpression

Conclusions

P21 functions are largely dependent on direct p21/protein interactions and p21 subcellular localizations. With regard to the p21 functions in cell cycle regulation, transcriptional regulation and modulation of apoptosis after DNA damaging it is better to focus on the factors that have critical roles in p21 expression, localization and activity, and among these, PI3K/Akt pathway and p53R2 can be the most important factor to investigate.

Conflict of interest

The authors declare that there are no conflicts of interest.

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ReviewMultiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage

Abstract

Introduction

Section snippets

Regulation of p21

p21 and cell cycle

p21 and apoptosis

Cytoplasmic p21

The relationship between p21 and p53R2

Correlation of p21 with PI3K/Akt/p21

Conclusions

Conflict of interest

J. Biol. Chem.

Life Sci.

Cancer Lett.

DNA Repair

Int. J. Biochem. Cell Biol.

Cell. Signal.

Cell

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Mol. Cell. Endocrinol.

Biochem. Biophys. Res. Commun.

Trends Biochem. Sci.

FEBS Lett.

J. Biol. Chem.

Int. J. Biochem. Cell Biol.

Biochim. Biophys. Acta

Mol. Aspects Med.

Toxicology

Neuroscience

Biochem. Biophys. Res. Commun.

Int. J. Biochem. Cell Biol.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Cell

Biochim. Biophys. Acta

Cancer Cell

Mol. Cell

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Exp. Cell Res.

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J. Biol. Chem.

Cell Metab.

Food Chem. Toxicol.

p21 in cancer: intricate networks and multiple activities

Nat. Rev. Cancer

Is p21 an oncogene?

Mol. Cancer Ther.

Control of cell cycle transcription during G1 and S phases

Nat. Rev. Mol. Cell Biol.

Rac1/p21-activated kinase pathway controls retinoblastoma protein phosphorylation and E2F transcription factor activation in B lymphocytes

FEBS J.

Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21

Nat. Chem. Biol.

P21-driven multifusion gene system for evaluating the efficacy of histone deacetylase inhibitors by in vivomolecular imaging and for transcription targeting therapy of cancer mediated by histone deacetylase inhibitor

J. Nucl. Med.

p21 exploits residue Tyr151 as a tether for high-affinity PCNA binding

Biochemistry

The p21 and PCNA partnership: a new twist for an old plot

Cell Cycle

Review
Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage