BRCA1 inhibition of telomerase activity in cultured cells.
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.
Xiong
Jingbo
J
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, USA.
Fan
Saijun
S
Meng
Qinghui
Q
Schramm
Laura
L
Wang
Chenguang
C
Bouzahza
Boumedienne
B
Zhou
Jinnian
J
Zafonte
Brian
B
Goldberg
Itzhak D
ID
Haddad
Bassem R
BR
Pestell
Richard G
RG
Rosen
Eliot M
EM
D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism; D001483:Base Sequence; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D015870:Gene Expression; D019398:Genes, BRCA1; D017930:Genes, Reporter; D016259:Genes, myc; D006801:Humans; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000378:metabolism
D019313:BRCA1 Protein; D017931:DNA Primers; D004268:DNA-Binding Proteins; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse