The LATS2/KPM tumor suppressor is a negative regulator of the androgen receptor
The LATS2/KPM tumor suppressor is a negative regulator of the androgen receptor
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DOI：
10.1210/me.2004-0065
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发表时间：
2004-08-01
影响因子：
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通讯作者：
Bai, C
中科院分区：
文献类型：
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作者：
Powzaniuk, M;McElwee-Witmer, S;Bai, C
雄激素受体 (AR) 是类固醇受体超家族的成员，在男性生殖系统的发育和维持以及前列腺癌中发挥着关键作用。 AR 的行为是通过与几类核心调节器的相互作用来控制的。在这项研究中，我们发现 LATS2/KPM 是一种新型 AR 相互作用蛋白。人类 LATS1 和 LATS2 是肿瘤抑制因子，与果蝇疣/拉特同源。 LATS2 的相互作用表面被映射到蛋白质的中心区域，而 AR 配体结合域足以实现这种相互作用。 LATS2 通过抑制雄激素调节的基因表达发挥 AR 调节剂的作用。 LATS2 介导的 AR 活性抑制机制似乎涉及抑制 AR NH2 和 COOH 末端相互作用。人前列腺癌细胞中的染色质免疫沉淀测定表明，LATS2 和 AR 存在于与前列腺特异性抗原的启动子和增强子区域结合的蛋白质复合物中，并且 LATS2 的过度表达导致雄激素诱导的内源性前列腺特异性抗原 mRNA 表达减少。免疫组织化学显示 LATS2 和 AR 位于前列腺上皮内，并且人前列腺肿瘤样本中的 LATS2 表达低于正常前列腺。结果表明，LATS2 可能在 AR 介导的转录中发挥作用，并有助于前列腺癌的发展。
The androgen receptor (AR) is a member of the steroid receptor superfamily that plays critical roles in the development and maintenance of the male reproductive system and in prostate cancer. Actions of AR are controlled by interaction with several classes of coregulators. In this study, we have identified LATS2/KPM as a novel AR-interacting protein. Human LATS1 and LATS2 are tumor suppressors that are homologs of Drosophila warts/lats. The interaction surface of LATS2 is mapped to the central region of the protein, whereas the AR ligand binding domain is sufficient for this interaction. LATS2 functions as a modulator of AR by inhibiting androgen-regulated gene expression. The mechanism of LATS2-mediated repression of AR activity appears to involve the inhibition of AR NH2- and COOH-terminal interaction. Chromatin immunoprecipitation assays in human prostate carcinoma cells reveal that LATS2 and AR are present in the protein complex that binds at the promoter and enhancer regions of prostate-specific antigen, and overexpression of LATS2 results in a reduction in androgen-induced expression of endogenous prostate-specific antigen mRNA. Immunohistochemistry shows that LATS2 and AR are localized within the prostate epithelium and that LATS2 expression is lower in human prostate tumor samples than in normal prostate. The results suggest that LATS2 may play a role in AR-mediated transcription and contribute to the development of prostate cancer.