TGF-beta1 inhibits BRCA1 expression through a pathway that requires pRb.
TGF-beta1 inhibits BRCA1 expression, which contradicts the model that TGF-beta1 prevents carcinogenesis by activating tumor suppressor genes. To resolve this apparent contradiction, we examined BRCA1 expression in Mv1Lu cells, a well-established model system for studying the TGF-beta1 tumor suppressor pathway. We found that inactivation of pRb by the papillomavirus type 16 E7 protein increased BRCA1 expression and abolished the ability of TGF-beta1 to inhibit BRCA1 expression. We conclude that TGF-beta1 inhibits BRCA1 expression through a pathway that requires pRb. We propose a model to explain the inhibition of BRCA1 as a target in the TGF-beta1 tumor suppressor signaling pathway. Our results suggest that the tumor suppressor functions of BRCA1 are initiated by the inactivation of pRb, and therefore that the activation of pRb by TGF-beta1 might alleviate the requirement for BRCA1 function.
Satterwhite
D J
DJ
Department of Pediatrics, Department of Oncological Sciences, University of Utah School of Medicine, 50 North Medical Drive, Salt Lake City, Utah 84132, USA. da,satterwhite@hsc.utah.edu
Matsunami
N
N
White
R L
RL
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics*; D002478:Cells, Cultured; D016193:G1 Phase / Q000187:drug effects* / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D008907:Mink; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D019313:BRCA1 Protein; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1