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First published on February 22, 2006; DOI: 10.1124/mol.105.020446

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Received for publication October 31, 2005.
Revised February 21, 2006.
Accepted for publication February 22, 2006.

hREV1 Modulates the Cytotoxicity and Mutagenicity of Cisplatin in Human Ovarian Carcinoma Cells

Xinjian Lin 1, Tsuyoshi Okuda 2, Julie Trang 3, Stephen B. Howell 1*

1 University of California - San Diego 2 Showa University School of Medicine 3 University of California, San Diego

* Address correspondence to: E-mail: showell{at}ucsd.edu

Abstract

REV1 interacts with Y-type DNA polymerases and Pol {zeta} to bypass many types of adducts that block the replicative DNA polymerases. This pathway accounts for many of the mutations induced by cisplatin (DDP). This study sought to determine how increasing hREV1 affects the cytotoxicity and mutagenicity of DDP. Human ovarian carcinoma 2008 cells were transfected with a hREV1 expression vector and 4 sublines developed in which hREV1 mRNA level was increased by 6.3 - 23.4-fold and hREV1 protein by 2.7 - 6.2-fold. The sublines were 1.3 - 1.7-fold resistant to the cytotoxic effect of DDP, and 2.3 - 5.1-fold hypersensitive to the mutagenic effect of DDP. The hREV1-transfected sublines were 1.5 - 1.8-fold better than the parental 2008 cells at managing DDP adducts as assessed by their ability to express Renilla luciferase from a vector that had been extensively loaded with DDP adducts prior to transfection. Increased hREV1 expression was associated with a 1.5-fold increase in the rate at which the whole population acquired resistance to DDP during sequential cycles of drug exposure. Increasing the abundance of hREV1 thus resulted in both resistance to DDP and a significant elevation in DDP-induced mutagenicity. This was accompanied by enhanced capacity to synthesize a functional protein from a DDP damaged gene and, most importantly, by more rapid development of resistance during sequential cycles of DDP exposure that mimic clinical schedules of DDP administration. We conclude that hREV1-dependent processes are important determinants of DDP-induced genomic instability and the development of resistance.


Key words: Regulation of gene expression, Overexpression, Resistance


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Home page
 Nucleic Acids ResHome page
J. A. Brown, S. A. Newmister, K. A. Fiala, and Z. Suo
Mechanism of double-base lesion bypass catalyzed by a Y-family DNA polymerase
Nucleic Acids Res., July 1, 2008; 36(12): 3867 - 3878.
[Abstract] [Full Text] [PDF]


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