Open AccessBRCA1 regulates transforming growth factor‐β (TGF‐β1) signaling through Gadd45a by enhancing the protein stability of Smad4
Author(s) -
Li Dan,
Kang Nan,
Ji Junfang,
Zhan Qimin
Publication year - 2015
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2015.05.002
Subject(s) - smad , microbiology and biotechnology , ubiquitin ligase , carcinogenesis , cell cycle checkpoint , cell cycle , biology , signal transduction , dna damage , regulator , ubiquitin , transforming growth factor , cancer research , apoptosis , gene , dna , genetics
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 SCFβ‐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.