Dehydroepiandrosterone sulfate mediates activation of transcription factors CREB and ATF-1 via a Gα11-coupled receptor in the spermatogenic cell line GC-2.
Dehydroepiandrosterone sulfate mediates activation of transcription factors CREB and ATF-1 via a Gα11-coupled receptor in the spermatogenic cell line GC-2.
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硫酸脱氢表雄酮通过生精细胞系 GC-2 中的 Gα11 偶联受体介导转录因子 CREB 和 ATF-1 的激活
DOI：
10.1016/j.bbamcr.2013.08.015
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Scheiner-Bobis G
中科院分区：
文献类型：
--
作者：
Shihan M;Kirch U;Scheiner-Bobis G
脱氢表雄酮硫酸盐(DHEAS)是一种在肾上腺皮质、脑和性腺产生的循环类固醇。虽然一系列研究证实了类固醇对大脑的神经保护作用，但令人惊讶的是，人们对DHEAS对生殖系统细胞的生理影响知之甚少。在这里，我们证明了DHEAS作用于生精细胞系GC-2，诱导了c-Src和ERK1/2的时间和浓度依赖性的磷酸化，并激活了激活转化因子-1(ATF-1)和环磷酸腺苷反应元件结合蛋白(CREB)的转录因子。这些作用与睾酮的非经典信号通路是一致的，提示DHEAS是一种前雄激素，为了发挥其生物学活性，它会转化为睾酮。然而，在GC-2细胞中没有检测到类固醇硫酸酯酶mRNA，并且DHEAS在通过小干扰RNA(SiRNA)沉默雄激素受体后明显地诱导ERK1/2、ATF-1和CREB的激活，这显然与这一假设相矛盾，并且使得DHEAS似乎不太可能在胞浆中被转化为不同的类固醇来激活所述的激酶和转录因子。相反，DHEAS诱导的信号转导可能是通过类固醇与膜结合的G蛋白偶联受体的相互作用来介导的，因为沉默鸟嘌呤核苷酸结合蛋白亚单位α-11(GnCREB 11)导致取消DHEAS诱导的ERK1/2、α-1和CREB的刺激。本文的研究显示DHEAS在生精细胞系上具有激素样活性。由于DHEAS是在男性和女性生殖器官中产生的，这些发现可能有助于确定DHEAS在生殖生理学中的新角色。
Dehydroepiandrosterone sulfate (DHEAS) is a circulating steroid produced in the adrenal cortex, brain, and gonads. Whereas a series of investigations attest to neuroprotective effects of the steroid in the brain, surprisingly little is known about the physiological effects of DHEAS on cells of the reproductive system. Here we demonstrate that DHEAS acting on the spermatogenic cell line GC-2 induces a time- and concentration-dependent phosphorylation of c-Src and Erk1/2 and activates the transcription factors activating transforming factor-1 (ATF-1) and cyclic AMP-responsive element binding protein (CREB). These actions are consistent with the non-classical signaling pathway of testosterone and suggest that DHEAS is a pro-androgen that is converted into testosterone in order to exert its biological activity. The fact, however, that steroid sulfatase mRNA was not detected in the GC-2 cells and the clear demonstration of DHEAS-induced activation of Erk1/2, ATF-1 and CREB after silencing the androgen receptor by small interfering RNA (siRNA) clearly contradict this assumption and make it appear unlikely that DHEAS has to be converted in the cytosol into a different steroid in order to activate the kinases and transcription factors mentioned. Instead, it is likely that the DHEAS-induced signaling is mediated through the interaction of the steroid with a membrane-bound G-protein-coupled receptor, since silencing of Guanine nucleotide-binding protein subunit alpha-11 (Gnα11) leads to the abolition of the DHEAS-induced stimulation of Erk1/2, ATF-1, and CREB. The investigation presented here shows a hormone-like activity of DHEAS on a spermatogenic cell line. Since DHEAS is produced in male and female reproductive organs, these findings could help to define new roles for DHEAS in the physiology of reproduction.
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