The Multifaceted p21 (Cip1/Waf1/CDKN1A) in Cell Differentiation, Migration and Cancer Therapy.

Kreis Kreis,Louwen Louwen,Yuan Yuan

doi:10.3390/cancers11091220

Abstract

Loss of cell cycle control is characteristic of tumorigenesis. The protein p21 is the founding member of cyclin-dependent kinase inhibitors and an important versatile cell cycle protein. p21 is transcriptionally controlled by p53 and p53-independent pathways. Its expression is increased in response to various intra- and extracellular stimuli to arrest the cell cycle ensuring genomic stability. Apart from its roles in cell cycle regulation including mitosis, p21 is involved in differentiation, cell migration, cytoskeletal dynamics, apoptosis, transcription, DNA repair, reprogramming of induced pluripotent stem cells, autophagy and the onset of senescence. p21 acts either as a tumor suppressor or as an oncogene depending largely on the cellular context, its subcellular localization and posttranslational modifications. In the present review, we briefly mention the general functions of p21 and summarize its roles in differentiation, migration and invasion in detail. Finally, regarding its dual role as tumor suppressor and oncogene, we highlight the potential, difficulties and risks of using p21 as a biomarker as well as a therapeutic target.

Highlights

Loss of cell cycle control is characteristic of tumorigenesis
As a critical effector of a variety of intra- and extracellular stress signals [8], p21 is exceedingly regulated by a myriad of transcriptional factors [9,10], distinct posttranscriptional regulators like microRNAs and RNA binding proteins [11] as well as various posttranslational modifications
Its cytoplasmic localization in mature myofibrils through phosphorylation at Ser-153 [75]. These data strongly highlight the notion that p21 is tightly involved in normal cell differentiation, whether it confers a positive or negative role depends on a number of factors including its expression level, postmodification, cell type, differentiation stage and cell microenvironment (Table 2)

Summary

Introduction

P21, encoded by the gene CDKN1A, is the founding member of cyclin-dependent kinase (Cdk) inhibitors (CKI) [1], a pivotal cell cycle regulator ensuring genomic stability and often deregulated in human cancer [2,3,4]. As a critical effector of a variety of intra- and extracellular stress signals [8], p21 is exceedingly regulated by a myriad of transcriptional factors [9,10], distinct posttranscriptional regulators like microRNAs (miRNAs) and RNA binding proteins [11] as well as various posttranslational modifications. Reversible protein phosphorylation by diverse kinases serves as an additional posttranslational mechanism controlling p210 s function, localization, binding partners, stability and degradation [3,13]. Phosphorylation at distinct sites by various kinases can cause the cytoplasmic translocation of p21 greatly affecting its functionality and the therapeutic response of many chemotherapeutic interventions [2,3,4,14,15,16].

Functions of p21

References *

Translating in Tumor Therapy

Lessons from Mouse Studies

Considering p21 in Cancer Therapy

Concepts of Targeting p21

Findings

Conclusions