DEAR1 is a chromosome 1p35 tumor suppressor and master regulator of TGF-β-driven epithelial-mesenchymal transition.
DEAR1 is a chromosome 1p35 tumor suppressor and master regulator of TGF-β-driven epithelial-mesenchymal transition.
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DOI：
10.1158/2159-8290.cd-12-0499
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发表时间：
2013-10
期刊：
影响因子：
28.2
通讯作者：
Killary AM
中科院分区：
文献类型：
--
作者：
Chen N;Balasenthil S;Reuther J;Frayna A;Wang Y;Chandler DS;Abruzzo LV;Rashid A;Rodriguez J;Lozano G;Cao Y;Lokken E;Chen J;Frazier ML;Sahin AA;Wistuba II;Sen S;Lott ST;Killary AM
Deletion of chromosome 1p35 is a common event in epithelial malignancies. We report that DEAR1 (annotated as TRIM62) is a chromosome 1p35 tumor suppressor that undergoes mutation, copy number variation and loss of expression in human tumors. Targeted disruption in the mouse recapitulates this human tumor spectrum with both Dear1−/− and Dear1+/− mice developing primarily epithelial adenocarcinomas and lymphoma with evidence of metastasis in a subset of mice. DEAR1 loss of function in the presence of TGFβ results in failure of acinar morphogenesis, upregulation of EMT markers, anoikis resistance, migration and invasion. Furthermore, DEAR1 blocks TGFβ-SMAD3 signaling resulting in decreased nuclear phosphorylated SMAD3 by binding to and promoting the ubiquitination of SMAD3, the major effector of TGFβ-induced EMT. Moreover, DEAR1 loss increases levels of SMAD3 downstream effectors, SNAI1 and SNAI2, with genetic alteration of DEAR1/SNAI2 serving as prognostic markers of overall poor survival in an 889 invasive breast cancer cohort.
