The Role of Cell Cycle Regulators in Cell Survival-Dual Functions of Cyclin-Dependent Kinase 20 and p21Cip1/Waf1.

Lo Lai,Ga Yoon Shin,Hongyu Qiu

doi:10.3390/ijms21228504

Lo Lai, Ga Yoon Shin + Show 1 more

Open Access

https://doi.org/10.3390/ijms21228504

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Abstract

The mammalian cell cycle is important in controlling normal cell proliferation and the development of various diseases. Cell cycle checkpoints are well regulated by both activators and inhibitors to avoid cell growth disorder and cancerogenesis. Cyclin dependent kinase 20 (CDK20) and p21Cip1/Waf1 are widely recognized as key regulators of cell cycle checkpoints controlling cell proliferation/growth and involving in developing multiple cancers. Emerging evidence demonstrates that these two cell cycle regulators also play an essential role in promoting cell survival independent of the cell cycle, particularly in those cells with a limited capability of proliferation, such as cardiomyocytes. These findings bring new insights into understanding cytoprotection in these tissues. Here, we summarize the new progress of the studies on these two molecules in regulating cell cycle/growth, and their new roles in cell survival by inhibiting various cell death mechanisms. We also outline their potential implications in cancerogenesis and protection in heart diseases. This information renews the knowledge in molecular natures and cellular functions of these regulators, leading to a better understanding of the pathogenesis of the associated diseases and the discovery of new therapeutic strategies.

Highlights

The cell cycle, called the cell-division cycle, has long been an intriguing research topic because of its importance in normal cell proliferation and cancerogenesis
Among the CDK-activating kinases (CAKs), Cyclin dependent kinase 20 (CDK20), previously known as cell cycle-related kinase (CCRK) [6], has been reported to have CAK activity for CDK2 to promote the transition from G1 to S phase
Studies have shown that CDK20 and p21Cip1/Waf1 serve as important regulators in tumorigenicity and are functionally connected to a broad range of cell signaling pathways with important functions in cell cycle progression, cell proliferation, and malignant transformation, indicating that these regulators may serve as novel prognostic markers and may be promising candidates as a molecular target for cancer therapy for some types of cancer

Summary

Introduction

The cell cycle, called the cell-division cycle, has long been an intriguing research topic because of its importance in normal cell proliferation and cancerogenesis. P21Cip1/Waf, known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, plays an opposite effect of CDK20 by inhibiting CDK2 activity, and functions as a negative regulator of cell cycle progression at G1 and S phase. Studies have shown that both CDK20 and p21Cip1/Waf play important roles in cell growth, such as cell proliferation, division, and hypertrophy via variant mechanisms [2,11,16,25,29,30,31]. Studies indicate that the effect of CDK20 in cell survival is in an isoform-dependent manner, while p21Cip1/Waf regulates multiple cell death signaling according to its subcellular localization

CDK20 in the Regulation in Cell Survival and Its Variants

Clinical Potential

Conclusions and Future Directions