Distinct roles for p53 transactivation and repression in preventing ucn-01-mediated abrogation of dna damage-induced arrest at s and g2 cell cycle checkpoints

ABSTRACT The topoisomerase I inhibitor SN38 arrests cell cycle progression primarily in S or G2 phases of the cell cycle in a p53-independent manner. The Chk1 inhibitor,

7-hydroxystaurosporine (UCN-01), overcomes both S and G2 arrest preferentially in cells mutated for p53, driving cells through a lethal mitosis and thereby enhancing cytotoxicity. The

mechanism by which p53 maintains S and G2 arrest was investigated here. The p53 wild-type MCF10A cells were arrested in S phase by incubation with SN38 for 24 h. Subsequent incubation with

UCN-01 failed to abrogate arrest. To examine the impact of p53, MCF10A cells were developed, which express the tetramerization domain of p53 to inhibit endogenous p53 function. These cells

were attenuated in SN38-mediated induction of p21WAF1 and UCN-01 induced S, but not G2 progression. In contrast, MCF10A cells expressing short hairpin RNA to ablate p53 expression underwent

both S and G2 phase progression with UCN-01. The difference in G2 progression was attributed to p53-mediated gene repression; the MCF10A cells expressing the tetramerization domain retained

p53 protein and repressed both cyclin B and Chk1, while cells ablated for p53 did not repress these proteins. Hence, inhibition of p53 activator function permits S phase abrogation, while

additional inhibition of p53 repressor function is required for abrogation of G2 arrest. These studies provide a mechanistic explanation for how this therapeutic strategy can selectively

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Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE ANTI-TUMOR EFFECT OF TRIFLURIDINE VIA INDUCTION OF ABERRANT MITOSIS IS UNAFFECTED BY MUTATIONS MODULATING P53 ACTIVITY

Article Open access 02 July 2024 DUAL ROLE OF P21 IN REGULATING APOPTOSIS AND MITOTIC INTEGRITY IN RESPONSE TO DOXORUBICIN IN COLON CANCER CELLS Article Open access 02 April 2025

PHARMACOLOGICAL INHIBITION OF CRYPTOCHROME AND REV-ERB PROMOTES DNA REPAIR AND CELL CYCLE ARREST IN CISPLATIN-TREATED HUMAN CELLS Article Open access 09 September 2021 REFERENCES * Banin S,

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early access to many of the phospho-specific antibodies used. This work was supported by National Institutes of Health Grant CA82220 and a Cancer Center Support Grant CA23108 to the Norris

Cotton Cancer Center. AAL was supported by a National Institutes of Health training Grant T3209658. EAK was supported by a fellowship from the Susan G Komen Breast Cancer Foundation. AUTHOR

INFORMATION Author notes * 3 These two authors contributed equally to this work AUTHORS AND AFFILIATIONS * Department of Pharmacology and Toxicology, Dartmouth Medical School, Lebanon, NH,

03756, USA Aime A Levesque, Ethan A Kohn, Edward Bresnick & Alan Eastman * Norris Cotton Cancer Center, One Medical Center Drive, Rubin Building Level 6, Lebanon, NH, 03756, USA Aime A

Levesque, Ethan A Kohn, Edward Bresnick & Alan Eastman Authors * Aime A Levesque View author publications You can also search for this author inPubMed Google Scholar * Ethan A Kohn View

author publications You can also search for this author inPubMed Google Scholar * Edward Bresnick View author publications You can also search for this author inPubMed Google Scholar * Alan

Eastman View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Levesque,

A., Kohn, E., Bresnick, E. _et al._ Distinct roles for p53 transactivation and repression in preventing UCN-01-mediated abrogation of DNA damage-induced arrest at S and G2 cell cycle

checkpoints. _Oncogene_ 24, 3786–3796 (2005). https://doi.org/10.1038/sj.onc.1208451 Download citation * Received: 09 January 2004 * Revised: 10 December 2004 * Accepted: 10 December 2004 *

Published: 14 March 2005 * Issue Date: 26 May 2005 * DOI: https://doi.org/10.1038/sj.onc.1208451 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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KEYWORDS * p53 tumor suppressor * topoisomerase I inhibitors * cell cycle checkpoints * UCN-01 * cyclin B