Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation
Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation
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DOI：
10.1038/sj.emboj.7600660
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发表时间：
2005-05-18
期刊：
影响因子：
11.4
通讯作者：
Boizet-Bonhoure, B
中科院分区：
文献类型：
--
作者：
Malki, S;Nef, S;Boizet-Bonhoure, B
在哺乳动物性腺发育过程中，转录因子SOX9的核输入/输出是Sry启动的决定睾丸的级联反应的关键步骤。在这项研究中，我们确定了在NT2/D1细胞中SOX9核转位的分子机制，该机制是由前列腺素D2(PGD2)信号通路通过刺激其腺苷环化酶偶联的DP1受体而介导的。我们发现，cAMP依赖的蛋白激酶A(PKA)的激活诱导了SOX9在其两个S64和S181 PKA位点上的磷酸化，并通过增强SOX9与核质运输蛋白Importinβ的结合来促进其核定位。此外，在胚胎性腺中，我们检测到男性特有的前列腺素D合成酶的表达和SOX9表达的时间和地点的活跃的PGD2信号。因此，我们提出了在性别决定级联中的新步骤，其中PGD2作为自分泌因子诱导SOX9核转位和随后的Sertoli细胞分化。
During mammalian gonadal development, nuclear import/export of the transcription factor SOX9 is a critical step of the Sry-initiated testis-determining cascade. In this study, we identify a molecular mechanism contributing to the SOX9 nuclear translocation in NT2/D1 cells, which is mediated by the prostaglandin D2 (PGD2) signalling pathway via stimulation of its adenylcyclase-coupled DP1 receptor. We find that activation of cAMP-dependent protein kinase A (PKA) induces phosphorylation of SOX9 on its two S64 and S181 PKA sites, and its nuclear localization by enhancing SOX9 binding to the nucleocytoplasmic transport protein importin beta. Moreover, in embryonic gonads, we detect a male-specific prostaglandin D synthase expression and an active PGD2 signal at the time and place of SOX9 expression. We thus propose a new step in the sex-determining cascade where PGD2 acts as an autocrine factor inducing SOX9 nuclear translocation and subsequent Sertoli cell differentiation.