title: BRCA1 regulates transforming growth factor-β (TGF-β1) signaling through Gadd45a by enhancing the protein stability of Smad4.
abstract: BRCA1 is a well established tumor suppressor gene, which is involved in many cellular processes, including DNA damage repair, cell cycle control, apoptosis, as well as transcriptional control. In this work, we have found that BRCA1 is involved in regulating TGF-β1/Smad pathway. The loss of endogenous BRCA1 greatly attenuated TGF-β1-induced growth inhibition and cell cycle G1 arrest. BRCA1 greatly maintains stability of Smad4 protein, and the loss of BRCA1 results in Smad4 down-regulation, which is likely related to its downstream gene Gadd45a. Gadd45a is able to interact with β-Trcp1, a-F-box protein of SCF E3 ligase, and consequently suppresses the ubiquitin-degradation of Smad4 by SCF(β-trcp1), as reflected by the observations that the induction of Gadd45a substantially stabilizes Smad4 protein. In addition, exogenous expression of Gadd45a can largely rescue the protein level of Smad4 in BRCA1 deficient cells. These results further demonstrate that BRCA1 may act as an important negative regulator in cell cycle progression and tumorigenesis through regulating the stability of Smad4, and define a novel link that connects BRCA1 to TGF-β1/Smad pathway.
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Kang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Junfang
authors.initials: J
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China. Electronic address: zhanqimin@pumc.edu.cn.
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhan
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000502:physiology*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology*; D055550:Protein Stability; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D051785:Smad Proteins; D051901:Smad4 Protein; D053773:Transforming Growth Factor beta1; C492913:BRCA1 protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C497796:SMAD4 protein, human; C508960:TGFB1 protein, human
keywords: BRCA1; Cell growth; Gadd45a; TGF-β1; Tumor suppressor gene; Tumorigenesis; Ubiquitin