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 Previous Article

Molecular and Cellular Biology, March 2004, p. 2202-2213, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.2202-2213.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Human Checkpoint Protein hRad9 Functions as a Negative Coregulator To Repress Androgen Receptor Transactivation in Prostate Cancer Cells

Liang Wang, Cheng-Lung Hsu, Jing Ni, Peng-Hui Wang, Shuyuan Yeh, Peter Keng, and Chawnshang Chang*

George H. Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and Cancer Center, University of Rochester Medical Center, Rochester, New York 14642

Received 8 October 2003/ Accepted 12 November 2003

Positive responses to combined androgen elimination therapy and radiation therapy have been well documented in the treatment of prostate cancer patients. The detailed mechanisms how androgen-androgen receptor (AR) cross talks to the radiation-related signal pathways, however, remain largely unknown. Here we report the identification of hRad9, a key member of the checkpoint Rad protein family, as a coregulator to suppress androgen-AR transactivation in prostate cancer cells. In vivo and in vitro interaction assays using Saccharomyces cerevisiae two-hybrid, mammalian two-hybrid, glutathione S-transferase pull-down, and coimmunoprecipitation methods prove that AR can interact with the C terminus of hRad9 via its ligand binding domain. The FXXLF motif within the C terminus of hRad9 interrupts the androgen-induced interaction between the N terminus and C terminus of AR. This interaction between AR and hRad9 may result in the suppression of AR transactivation, demonstrated by the repressed AR transactivation in androgen-induced luciferase reporter assay and the reduced endogenous prostate-specific antigen expression in Western blot assay. Addition of small interfering RNA of hRad9 can reverse hRad9 suppression effects, which suggests that hRad9 functions as a repressor of AR transactivation in vivo. Together, our data provide the first linkage between androgen-AR signals and radiation-induced responses. Further studies of the influence of hRad9 on prostate cancer growth may provide potential new therapeutic approaches.

* Corresponding author. Mailing address: George H. Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, 601 Elmwood Ave., Box 626, Rochester, NY 14642. Phone: (585) 275-9994. Fax: (585) 756-4133. E-mail: chang{at}URMC.rochester.edu.

Molecular and Cellular Biology, March 2004, p. 2202-2213, Vol. 24, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.5.2202-2213.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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