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      The Role of the Cyclin Dependent Kinase Inhibitor p21 cip1/waf1 in Targeting Cancer: Molecular Mechanisms and Novel Therapeutics

      review-article
      Author(s): , *
      Publication date (Electronic):
      Journal: Cancers
      Publisher: MDPI
      Keywords: p21, signaling pathways, cell cycle, dual role, cancer therapy, chemoresistance

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          Abstract

          p21 cip1/waf1 mediates various biological activities by sensing and responding to multiple stimuli, via p53-dependent and independent pathways. p21 is known to act as a tumor suppressor mainly by inhibiting cell cycle progression and allowing DNA repair. Significant advances have been made in elucidating the potential role of p21 in promoting tumorigenesis. Here, we discuss the involvement of p21 in multiple signaling pathways, its dual role in cancer, and the importance of understanding its paradoxical functions for effectively designing therapeutic strategies that could selectively inhibit its oncogenic activities, override resistance to therapy and yet preserve its tumor suppressive functions.

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          Requirement for p53 and p21 to sustain G2 arrest after DNA damage.

          F Bunz, A Dutriaux, C Lengauer … (1998)
          After DNA damage, many cells appear to enter a sustained arrest in the G2 phase of the cell cycle. It is shown here that this arrest could be sustained only when p53 was present in the cell and capable of transcriptionally activating the cyclin-dependent kinase inhibitor p21. After disruption of either the p53 or the p21 gene, gamma radiated cells progressed into mitosis and exhibited a G2 DNA content only because of a failure of cytokinesis. Thus, p53 and p21 appear to be essential for maintaining the G2 checkpoint in human cells.
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            PCNA, the maestro of the replication fork.

            George-Lucian Moldovan, Boris Pfander, Stefan Jentsch (2007)
            Inheritance requires genome duplication, reproduction of chromatin and its epigenetic information, mechanisms to ensure genome integrity, and faithful transmission of the information to progeny. Proliferating cell nuclear antigen (PCNA)-a cofactor of DNA polymerases that encircles DNA-orchestrates several of these functions by recruiting crucial players to the replication fork. Remarkably, many factors that are involved in replication-linked processes interact with a particular face of PCNA and through the same interaction domain, indicating that these interactions do not occur simultaneously during replication. Switching of PCNA partners may be triggered by affinity-driven competition, phosphorylation, proteolysis, and modification of PCNA by ubiquitin and SUMO.
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              Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage.

              Ansar Karimian, Seyyed Amir Yasin Ahmadi, Bahman Yousefi (2016)
              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.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancers (Basel)
                Journal ID (iso-abbrev): Cancers (Basel)
                Journal ID (publisher-id): cancers
                Title: Cancers
                Publisher: MDPI
                ISSN (Electronic): 2072-6694
                Publication date (Electronic): 30 September 2019
                Publication date Collection: October 2019
                Volume: 11
                Issue: 10
                Electronic Location Identifier: 1475
                Affiliations
                Department of Biology, and Center for Drug Discovery, American University of Beirut, Beirut 1103, Lebanon; sfa28@ 123456mail.aub.edu
                Author notes
                [* ]Correspondence: amro@ 123456aub.edu.lb ; Tel.: +961-397-3820
                Author information
                https://orcid.org/0000-0001-6840-3015
                Article
                Publisher ID: cancers-11-01475
                DOI: 10.3390/cancers11101475
                PMC ID: 6826572
                PubMed ID: 31575057
                SO-VID: 1e49932e-171c-4b7a-af0d-10cebeaedb61
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 18 June 2019
                Date accepted : 30 July 2019
                Categories
                Subject: Review

                Keywords: p21,signaling pathways,cell cycle,dual role,cancer therapy,chemoresistance
                Data availability:
                Keywords: p21, signaling pathways, cell cycle, dual role, cancer therapy, chemoresistance

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