14-3-3 zeta Turns TGF- beta 's Function from Tumor Suppressor to Metastasis Promoter in Breast Cancer by Contextual Changes of Smad Partners from p53 to Gli2

Transforming growth factor beta (TGF- beta ) functions as a tumor suppressor in premalignant cells but as a metastasis promoter in cancer cells. The dichotomous functions of TGF- beta are proposed to be dictated by different partners of its downstream effector Smads. However, the mechanism for the c...

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Veröffentlicht in:Cancer cell 2015-02, Vol.27 (2), p.177-192
Hauptverfasser: Xu, Jia, Acharya, Sunil, Sahin, Ozgur, Zhang, Qingling, Saito, Yohei, Yao, Jun, Wang, Hai, Li, Ping, Zhang, Lin, Lowery, Frank J, Kuo, Wen-Ling, Xiao, Yi, Ensor, Joe, Sahin, Aysegul A, Zhang, Xiang H-F, Hung, Mien-Chie, Zhang, Jitao David, Yu, Dihua
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container_end_page 192
container_issue 2
container_start_page 177
container_title Cancer cell
container_volume 27
creator Xu, Jia
Acharya, Sunil
Sahin, Ozgur
Zhang, Qingling
Saito, Yohei
Yao, Jun
Wang, Hai
Li, Ping
Zhang, Lin
Lowery, Frank J
Kuo, Wen-Ling
Xiao, Yi
Ensor, Joe
Sahin, Aysegul A
Zhang, Xiang H-F
Hung, Mien-Chie
Zhang, Jitao David
Yu, Dihua
description Transforming growth factor beta (TGF- beta ) functions as a tumor suppressor in premalignant cells but as a metastasis promoter in cancer cells. The dichotomous functions of TGF- beta are proposed to be dictated by different partners of its downstream effector Smads. However, the mechanism for the contextual changes of Smad partners remained undefined. Here, we demonstrate that 14-3-3 zeta destabilizes p53, a Smad partner in premalignant mammary epithelial cells, by downregulating 14-3-3 sigma , thus turning off TGF- beta 's tumor suppression function. Conversely, 14-3-3 zeta stabilizes Gli2 in breast cancer cells, and Gli2 partners with Smads to activate PTHrP and promote TGF- beta -induced bone metastasis. The 14-3-3 zeta -driven contextual changes of Smad partners from p53 to Gli2 may serve as biomarkers and therapeutic targets of TGF- beta -mediated cancer progression.
doi_str_mv 10.1016/j.ccell.2014.11.025
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title 14-3-3 zeta Turns TGF- beta 's Function from Tumor Suppressor to Metastasis Promoter in Breast Cancer by Contextual Changes of Smad Partners from p53 to Gli2
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