Steroid-induced androgen receptor-oestradiol receptor β-Src complex triggers prostate cancer cell proliferation
Steroid-induced androgen receptor-oestradiol receptor β-Src complex triggers prostate cancer cell proliferation
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DOI：
10.1093/emboj/19.20.5406
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发表时间：
2000-10-16
期刊：
影响因子：
11.4
通讯作者：
Auricchio, F
中科院分区：
文献类型：
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作者：
Migliaccio, A;Castoria, G;Auricchio, F
人前列腺癌LNCaP细胞用雄激素或雌二醇处理后，雄激素受体和雌二醇受体β同时与Src结合，激活Src/Raf-1/Erk-2通路，刺激细胞增殖。令人惊讶的是，雄激素或雌二醇对这些步骤中的每一步的作用都被抗雄激素和抗雌激素抑制。在雌激素或雄激素刺激的MCF-7或T47D细胞中，也观察到类似的雌二醇受体α的发现。微量注射SrcK(-)的LNCaP、MCF7和T47D细胞可阻断激素刺激的S时相进入。来自转基因Cos细胞的数据证实并扩展了来自这些细胞的发现。使用谷胱甘肽S-转移酶融合构建物检测激素刺激的Src与雄激素受体和雌二醇受体α或β的相互作用。SRCSH2与雌二醇受体α的磷酸酪氨酸537相互作用，而Src SH3结构域与雄激素受体的一段富含脯氨酸的片段相互作用。在完整的Cos细胞中，这种磷酸酪氨酸需要雌二醇受体α与Src结合，从而激活Src，从而强调了它的作用。
Treatment of human prostate carcinoma-derived LNCaP cells with androgen or oestradiol triggers simultaneous association of androgen receptor and oestradiol receptor beta with Src, activates the Src/Raf-1/Erk-2 pathway and stimulates cell proliferation. Surprisingly, either androgen or oestradiol action on each of these steps is inhibited by both anti-androgens and anti-oestrogens. Similar findings for oestradiol receptor alpha were observed in MCF-7 or T47D cells stimulated by either oestradiol or androgens. Microinjection of LNCaP, MCF-7 and T47D cells with SrcK(-) abolishes steroid-stimulated S-phase entry. Data-from transfected Cos cells confirm and extend the findings from these cells. Hormone-stimulated Src interaction with the androgen receptor and oestradiol receptor alpha or beta is detected using glutathione S-transferase fusion constructs. Src SH2 interacts with phosphotyrosine 537 of oestradiol receptor alpha and the Src SH3 domain with a proline-rich stretch of the androgen receptor. The role of this phosphotyrosine is stressed by its requirement for association of oestradiol receptor alpha with Src and consequent activation of Src in intact Cos cells.