Ahnak functions as a tumor suppressor via modulation of TGFβ/Smad signaling pathway.
Ahnak functions as a tumor suppressor via modulation of TGFβ/Smad signaling pathway.
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Ahnak 通过调节 TGFβ/Smad 信号通路发挥肿瘤抑制因子的作用。
作者：
我们提供了Ahnak介导的转化生长因子β（TGFβ）信号转导增强的详细机制，其导致细胞生长的负调节。我们发现Smad 3通过MH 2结构域与Ahnak相互作用，Ahnak刺激Smad 3定位到细胞核中，从而增强TGFβ诱导的R-Smad转录活性。此外，Ahnak的过表达通过下调c-Myc和cyclin D1/D2而导致生长迟缓和细胞周期停滞。我们描述了以乳腺特异性方式表达中间T抗原的Ahnak−/−小鼠模型（MMTVTg/+Ahnak−/−）的分析结果，与MMTVTg/+Ahnak+/+相比，该模型显示乳腺增生显著进展。最后，我们筛选了多个人乳腺癌组织，并显示癌组织中Ahnak的表达比对照组织低50%。综上所述，这些数据表明Ahnak介导细胞生长的负调节，并通过增强TGFβ信号传导作为新的肿瘤抑制剂。
We provide detailed mechanisms of Ahnak-mediated potentiation of transforming growth factor β (TGFβ) signaling, which leads to a negative regulation of cell growth. We show that Smad3 interacts with Ahnak through MH2 domain and that Ahnak stimulates Smad3 localization into nucleus leading to potentiating TGFβ-induced transcriptional activity of R-Smad. Moreover, overexpression of Ahnak resulted in growth retardation and cell cycle arrest through downregulation of c-Myc and cyclin D1/D2. We describe results from analyses of Ahnak−/− mouse model expressing middle T antigen in a mammary gland-specific manner (MMTVTg/+Ahnak−/−), which showed significantly progressed hyperplasia of mammary glands compared with MMTVTg/+Ahnak+/+. Finally, we screened multiple human breast cancer tissues and showed that the expression of Ahnak in cancer tissues is lower than that in control tissues by 50%. Taken together, these data indicate that Ahnak mediates a negative regulation of cell growth and acts as novel tumor suppressor through potentiation of TGFβ signaling.
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DOI：
10.1158/1055-9965.epi-11-0062
发表时间：
2011-06
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Scollen S;Luccarini C;Baynes C;Driver K;Humphreys MK;Garcia-Closas M;Figueroa J;Lissowska J;Pharoah PD;Easton DF;Hesketh R;Metcalfe JC;Dunning AM
通讯作者：
Dunning AM
影响因子：
4.8
作者：
Lee, In Hye;Lim, Hee Jung;Bae, Yun Soo
通讯作者：
Bae, Yun Soo
影响因子：
64.5
作者：
Pelengaris, S;Khan, M;Evan, GI
通讯作者：
Evan, GI
影响因子：
8
作者：
Morikawa, M.;Koinuma, D.;Miyazono, K.;Heldin, C-H
通讯作者：
Heldin, C-H
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW