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DNA damage-induced cell cycle checkpoints as a target for cancer therapy.

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Call No.	RC268.4 .K64 2003
Author	Kohn, Ethan Alfred.
Title	DNA damage-induced cell cycle checkpoints as a target for cancer therapy.
Date	2003
Abstract	Cells respond to DNA damage by activating signal transduction pathways that cause cell cycle arrest at checkpoints in G 1 , S, or G 2 phases of the cell cycle; this allows time for repair of damaged DNA. The G 1 checkpoint is dependent upon the function of the p53 tumor suppressor, whereas S and G 2 checkpoints are activated independently of p53. Prior studies showed that p53-defective cells that arrest in S and G 2 , but not p53 wild-type cells, can be sensitized to DNA damage by the checkpoint inhibitor caffeine, which causes premature cell cycle progression and lethal mitosis. This laboratory previously demonstrated that UCN-01, an inhibitor of Chk1/2 activity, also abrogates G 2 arrest and sensitizes p53-defective cells to DNA damage. The G 2 checkpoint involves the inhibition of the Cdc25C phosphatase by the Chk1 and Chk2 kinases; however, the mechanism of the S phase checkpoint has remained unclear. Here, we examined the mechanism of S phase arrest induced by the topoisomerase I inhibitor SN38 in p53-defective breast cancer cells and p53 wild-type breast cells. It was found that Cdc25C is not the critical target of Chk1/2 in S phase; rather, the S phase checkpoint functions through the Chk1-Cdc25A-cyclin E/Cdk2 pathway. UCN-01 induced S and G 2 progression in the p53-defective MDA-MB-231 cells at low nanomolar concentrations, whereas higher concentrations caused lethal mitosis without cell cycle progression, likely due to inhibition of C-TAK 1. Other novel, structurally related checkpoint inhibitors ICP-1 and Gö6976 also abrogated arrest, but did not appear to inhibit C-TAK1. These analogs differ from UCN-01 in that their potency was not inhibited by human serum proteins. In p53 wild-type cells, S phase arrest was maintained in the presence of UCN-01, by p53-mediated transcriptional activation of target genes such as p21. G 2 arrest was also maintained in p53 wild-type cells, by p53-mediated repression of genes such as cyclin B. These studies provide insight into the mechanism of the p53-independent S phase checkpoint, and the role of p53 in protecting cells against checkpoint inhibition. These results will facilitate the development of checkpoint inhibitors as anticancer drugs.
Description	xvi, 223 leaves : ill. 28 cm.
Format	application/pdf
Advisor	Alan Eastman.
Subject	Cancer cells -- Proliferation -- Molecular aspects. Biological control systems. Cancer cells -- Growth -- Regulation. Breast -- Cancer -- Genetic aspects. p53 protein. Cell cycle. DNA damage. Cellular signal transduction. Carcinogenesis -- Molecular aspects. Cell cycle proteins.
College	Dartmouth Medical School -- Department of Pharmacology and Toxicology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.26

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	DNA DAMAGE-INDUCED CELL CYCLE CHECKPOINTS AS A TARGET FOR CANCER THERAPY A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacology and Toxicology by Ethan Alfred Kohn DARTMOUTH COLLEGE Hanover, New Hampshire November 7th, 2003 Examining Committee: _________________________ (chair) Dr. Alan Eastman _________________________ Dr. Joshua Hamilton _________________________ Dr. Chris Lowrey _________________________ Dr. Michael Spinella _________________________ Dr. Edward Sausville _________________________ Dr. Carol Folt Dean of Graduate Studies

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