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Cell Growth & Differentiation Vol. 12, 243-254, May 2001
© 2001 American Association for Cancer Research

Overexpressed Human RAD50 Exhibits Cell Death in a p21WAF1/CIP1-dependent Manner

Its Potential Utility in Local Gene Therapy of Tumor1

Boo Ahn Shin2, Kyu Youn Ahn2, Hyun Kook2, Jeong Tae Koh, In Cheol Kang, Hyun Chul Lee and Kyung Keun Kim3

Research Institute of Medical Sciences [B. A. S., K. Y. A., H. K., H. C. L., K. K. K.], and Dental Science Research Institute [J. T. K., I. C. K., K. K. K.], Chonnam National University, Kwangju 501-190, South Korea

Previously, mouse RAD50, one of the mammalian DNA recombination repair genes, was reported to have limited epitopic homology to p53. Here we report the functional characteristics of overexpressed human RAD50 (hRAD50). Transient transfection of hRAD50 in several cultured cells caused cytotoxicity. We established tetracycline-regulated, stable hRAD50 expression systems in SaOS-2 cells, which retain mutated p53, and in HeLa cells. After tetracycline withdrawal, cell death and multinucleated giant cells were observed with increased hRAD50 expression, and p21WAF1/CIP1 but not p53 was increased. Transient transfection of hRAD50 in HCT116 p21-/- cells caused no cytotoxicity, but there was a significantly decreased survival rate in p21+/+ cells. These cytotoxic effects of overexpressed hRAD50 in HeLa, SaOS-2, and HCT116 p21+/+ cells were partially blocked by pretreatment of cells with N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a pan-caspase inhibitor. When the hRAD50 expression cDNA was injected intratumorally with liposomes, it regressed or delayed tumor development in the animal model and nitric oxide synthase expression was induced in the tumor tissues that had regressed. Our results indicate that overexpressed hRAD50 has an antiproliferation activity in vitro and in vivo in a p21-dependent manner.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 2001 by the American Association of Cancer Research.