title: BRCA1 inhibition of telomerase activity in cultured cells.
abstract: 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.
authors: 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.
authors: Jingbo
authors: J
authors: Xiong
authors: Saijun
authors: S
authors: Fan
authors: Qinghui
authors: Q
authors: Meng
authors: Laura
authors: L
authors: Schramm
authors: Chenguang
authors: C
authors: Wang
authors: Boumedienne
authors: B
authors: Bouzahza
authors: Jinnian
authors: J
authors: Zhou
authors: Brian
authors: B
authors: Zafonte
authors: Itzhak D
authors: ID
authors: Goldberg
authors: Bassem R
authors: BR
authors: Haddad
authors: Richard G
authors: RG
authors: Pestell
authors: Eliot M
authors: EM
authors: Rosen
mesh_terms: 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
chemical_list: D019313:BRCA1 Protein; D017931:DNA Primers; D004268:DNA-Binding Proteins; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse