Testosterone activates mitogen-activated protein kinase and the cAMP response element binding protein transcription factor in Sertoli cells
Testosterone activates mitogen-activated protein kinase and the cAMP response element binding protein transcription factor in Sertoli cells
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DOI：
10.1073/pnas.0404278101
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发表时间：
2004-07-27
影响因子：
11.1
通讯作者：
Walker, WH
中科院分区：
文献类型：
--
作者：
Fix, C;Jordan, C;Walker, WH
雄激素睾酮是支持细胞支持雄性生殖细胞成熟和精子产生（精子发生）所必需的。在雄激素作用的经典观点中，雄激素与细胞内雄激素受体（AR）的结合产生AIR的构象变化，使得受体-类固醇复合物对特异性DNA调节元件具有高亲和力，并且能够刺激基因转录。在这里，我们证明了睾酮可以通过一种替代的，快速的和可持续的机制在支持细胞中起作用，这种机制独立于AR-DNA相互作用。具体而言，向支持细胞中添加生理水平的睾酮刺激促分裂原活化蛋白激酶信号传导途径，并导致cAMP反应元件结合蛋白转录因子在丝氨酸133上的磷酸化，这是支持细胞支持精子发生所需的已知修饰。雄激素介导的丝裂原活化蛋白激酶和cAMP反应元件结合蛋白的激活在1分钟内发生，持续至少12小时，并需要AR。此外，雄激素诱导内源性cAMP反应元件结合蛋白介导的转录支持细胞。这些新发现的雄激素在支持细胞中的作用机制为开发男性避孕药提供了新的靶点。
The androgen testosterone is essential for the Sertoli cell to support the maturation of male germ cells and the production of spermatozoa (spermatogenesis). In the classical view of androgen action, binding of androgen to the intracellular androgen receptor (AR) produces a conformational change in AIR such that the receptor-steroid complex has high affinity for specific DNA regulatory elements and is able to stimulate gene transcription. Here, we demonstrate that testosterone can act by means of an alternative, rapid, and sustainable mechanism in Sertoli cells that is independent of AR-DNA interactions. Specifically, the addition of physiological levels of testosterone to Sertoli cells stimulates the mitogen-activated protein kinase signaling pathway and causes phosphorylation of the cAMP response element binding protein transcription factor on serine 133, a modification known to be required for Sertoli cells to support spermatogenesis. Androgen-mediated activation of mitogen-activated protein kinase and cAMP response element binding protein occurs within 1 min, extends for at least 12 h and requires AR. Furthermore, androgen induces endogenous cAMP response element binding protein-mediated transcription in Sertoli cells. These newly identified mechanisms of androgen action in Sertoli cells suggest new targets for developing male contraceptive agents.