DEAR1, a novel tumor suppressor that regulates cell polarity and epithelial plasticity.
DEAR1, a novel tumor suppressor that regulates cell polarity and epithelial plasticity.
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DOI：
10.1158/0008-5472.can-14-1171
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发表时间：
2014-10-15
期刊：
影响因子：
11.2
通讯作者：
Killary AM
中科院分区：
文献类型：
--
作者：
Chen N;Balasenthil S;Reuther J;Killary AM
阐明上皮可塑性的调节控制不仅对于更好地理解转移的性质至关重要，而且对于设计靶向治疗以防止原发性肿瘤迁移和侵袭的最早步骤也至关重要。本文将重点介绍新型TRIM蛋白DEAR 1（注释为TRIM 62）在调节顶基极性和腺泡形态发生中的作用，以及其作为染色体1 p35肿瘤抑制因子和TGFβ驱动的上皮-间质转化（EMT）负调节因子的功能。DEAR 1结合并促进SMAD 3的泛素化，SMAD 3是TGFβ介导的EMT的主要效应子，以及下调SMAD 3靶向SNAIL 1/2，EMT的主要转录调节因子。累积的结果表明，DEAR 1在乳腺肿瘤微环境，极性和EMT的调节中有一种新的模式。由于DEAR 1在包括乳腺癌在内的多种上皮癌中经历功能缺失突变、纯合缺失以及拷贝数损失，因此DEAR 1具有作为预测和预后生物标志物以及用于对乳腺癌和潜在的其他上皮肿瘤类型进行分层的临床实用性，以用于针对由DEAR 1调节的途径的靶向治疗。
Elucidation of the regulatory controls on epithelial plasticity is pivotal not only to better understand the nature of metastasis, but also for the design of targeted therapies to prevent the earliest steps in migration and invasion from the primary tumor. This review will highlight the role of the novel TRIM protein DEAR1 (annotated as TRIM62) in the regulation of apical-basal polarity and acinar morphogenesis as well as its function as a chromosome 1p35 tumor suppressor and negative regulator of TGFβ-driven epithelial-mesenchymal transition (EMT). DEAR1 binds to and promotes the ubiquitination of SMAD3, the major effector of TGFβ-mediated EMT, as well as downregulates SMAD3 targets SNAIL1/2, master transcriptional regulators of EMT. Cumulative results suggest a novel paradigm for DEAR1 in the regulation of the breast tumor microenvironment, polarity and EMT. Because DEAR1 undergoes loss of function mutations, homozygous deletion as well as copy number losses in multiple epithelial cancers including breast cancer, DEAR1 has clinical utility as a predictive and prognostic biomarker as well as for stratifying breast cancers and potentially other epithelial tumor types for targeted therapies aimed at the pathways regulated by DEAR1.
影响因子：
15.8
作者：
Muthuswamy SK
通讯作者：
Muthuswamy SK