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Molecular and Cellular Biology, December 2003, p. 8668-8690, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8668-8690.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

BRCA1 Inhibition of Telomerase Activity in Cultured Cells

Jingbo Xiong,1 Saijun Fan,2 Qinghui Meng,2 Laura Schramm,1 Chenguang Wang,2 Boumedienne Bouzahza,2 Jinnian Zhou,2 Brian Zafonte,3 Itzhak D. Goldberg,1 Bassem R. Haddad,2 Richard G. Pestell,2 and Eliot M. Rosen2*

Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040,1 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461,3 Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, D.C. 200572

Received 28 May 2003/ Returned for modification 10 July 2003/ Accepted 15 August 2003

Telomerase, an enzyme that maintains telomere length, plays major roles in cellular immortalization and cancer progression. We found that an exogenous BRCA1 gene strongly inhibited telomerase enzymatic activity in human prostate and breast cancer cell lines and caused telomere shortening in cell lines expressing wild-type BRCA1 (wtBRCA1) but not a tumor-associated mutant BRCA1 (T300G). wtBRCA1 inhibited the expression of the catalytic subunit (telomerase reverse transcriptase [TERT]) but had no effect on the expression of a subset of other components of the telomerase holoenzyme or on the expression of c-Myc, a transcriptional activator of TERT. However, endogenous BRCA1 associated and partially colocalized with c-Myc; exogenous wtBRCA1 strongly suppressed TERT promoter activity in various cell lines. The TERT inhibition was due, in part, to suppression of c-Myc E-box-mediated transcriptional activity. Suppression of TERT promoter and c-Myc activity required the amino terminus of BRCA1 but not the carboxyl terminus. Finally, endogenous BRCA1 and c-Myc were detected on transfected mouse and human TERT promoter segments in vivo. We postulate that inhibition of telomerase may contribute to the BRCA1 tumor suppressor activity.

* Corresponding author. Mailing address: Department of Oncology, Lombardi Cancer Center, Georgetown University, Preclinical Sciences Bldg., Room GM12B, 3970 Reservoir Rd., NW, Washington, DC 20007. Phone: (202) 687-7695. Fax: (202) 687-7505. E-mail: emr36{at}georgetown.edu.

Molecular and Cellular Biology, December 2003, p. 8668-8690, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8668-8690.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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