Cyclin D1: Mechanism and consequence of androgen receptor co-repressor activity
Cyclin D1: Mechanism and consequence of androgen receptor co-repressor activity
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DOI：
10.1074/jbc.m106399200
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发表时间：
2002-01-18
影响因子：
4.8
通讯作者：
Knudsen, KE
中科院分区：
文献类型：
--
作者：
Petre, CE;Wetherill, YB;Knudsen, KE
雄激素受体的调节对前列腺的生长发育至关重要。受体的激活是通过与雄激素(配体)的结合以及与共激活物和共抑制物的相互作用来决定的。我们以前已经证明，细胞周期蛋白D1是一种抑制配体依赖的雄激素受体激活的辅助抑制因子。我们证明了细胞周期蛋白D1直接与雄激素受体的N末端结合，并且这种相互作用不依赖于配体。此外，我们还证明了这种相互作用发生在细胞核内，并且不需要细胞周期蛋白D1的LxxLL基序。尽管在N端存在两个不同的反式激活结构域(AF-1和AF-5)，但所显示的数据支持Cyclin 131靶向AF-1反式激活功能的假设。结构活性的AF-5结构域对细胞周期蛋白D1的抑制不敏感。相比之下，细胞周期蛋白D1完全取消了雄激素受体的活性，即使在强大的雄激素受体共激动剂存在的情况下也是如此。细胞周期蛋白131的这种作用至少部分需要脱乙酰酶活性。最后，我们发现，在雄激素依赖的LNCaP细胞中，细胞周期蛋白DI的瞬时、异位表达导致细胞周期进程减少，而不依赖于CDK4的关联。总的来说，我们的数据支持这样一个模型，在该模型中，细胞周期蛋白D1具有促有丝分裂功能(依赖于CDK4)和抗有丝分裂功能(依赖于AF-1结构域的调节)，这两种功能可以共同控制雄激素依赖的细胞增殖速度。这些发现为深入了解细胞周期蛋白131的非细胞周期功能提供了动力，并为研究其在雄激素依赖细胞，特别是前列腺癌中的多效性作用提供了动力。
Androgen receptor regulation is pivotal for prostate growth and development. Activation of the receptor is dictated by association with androgen (ligand) and through interaction with co-activators and co-repressors. We have shown previously that cyclin D1 functions as a co-repressor to inhibit ligand-dependent androgen receptor activation. We demonstrate that cyclin D1 directly binds the N terminus of the androgen receptor and that this interaction is independent of ligand. Furthermore, we show that the interaction occurs in the nucleus and does not require the LXXLL motif of cyclin D1. Although two distinct transactivation domains exist in the N terminus (AF-1 and AF-5), the data shown support the hypothesis that cyclin 131 targets the AF-1 transactivation function. The constitutively active AF-5 domain was refractory to cyclin D1 inhibition. By contrast, cyclin D1 completely abolished androgen receptor activity, even in the presence of potent androgen receptor co-activators. This action of cyclin 131 at least partially required de-acetylase activity. Finally, we show that transient, ectopic expression of cyclin D I results in reduced cell cycle progression in androgen-dependent LNCaP cells independent of CDK4 association. Collectively, our data support a model wherein cyclin D1 has a mitogenic (CDK4-dependent) function and an anti-mitogenic function (dependent on regulation of the AF-1 domain) that can collectively control the rate of androgen-dependent cellular proliferation. These findings provide insight into the non-cell cycle functions of cyclin 131 and provide the impetus to study its pleiotropic effects in androgen-dependent cells, especially prostatic adenocarcinomas.