Xiong Jingbo, Fan Saijun, Meng Qinghui, Schramm Laura, Wang Chenguang, Bouzahza Boumedienne, Zhou Jinnian, Zafonte Brian, Goldberg Itzhak D, Haddad Bassem R, Pestell Richard G, Rosen Eliot M
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.
Mol Cell Biol. 2003 Dec;23(23):8668-90. doi: 10.1128/MCB.23.23.8668-8690.2003.
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.
端粒酶是一种维持端粒长度的酶，在细胞永生化和癌症进展中起主要作用。我们发现，外源性BRCA1基因在人前列腺癌和乳腺癌细胞系中强烈抑制端粒酶活性，并在表达野生型BRCA1（wtBRCA1）而非肿瘤相关突变型BRCA1（T300G）的细胞系中导致端粒缩短。wtBRCA1抑制催化亚基（端粒酶逆转录酶[TERT]）的表达，但对端粒酶全酶其他成分的一个子集的表达或对TERT的转录激活因子c-Myc的表达没有影响。然而，内源性BRCA1与c-Myc相互作用并部分共定位；外源性wtBRCA1在各种细胞系中强烈抑制TERT启动子活性。TERT的抑制部分归因于对c-Myc E盒介导的转录活性的抑制。抑制TERT启动子和c-Myc活性需要BRCA1的氨基末端而非羧基末端。最后，在体内转染的小鼠和人TERT启动子片段上检测到内源性BRCA1和c-Myc。我们推测，端粒酶的抑制可能有助于BRCA1的肿瘤抑制活性。
