Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene
Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene
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DOI：
10.1128/mcb.18.11.6653
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发表时间：
1998-11-01
影响因子：
5.3
通讯作者：
Berta, P
中科院分区：
文献类型：
--
作者：
De Santa Barbara, P;Bonneaud, N;Berta, P
为了正确的男性性别分化，在胚胎发育过程中必须严格调控抗苗勒氏激素(AMH)，以促进苗勒管的退化。然而，雄性哺乳动物AMH发病的分子机制尚不清楚。类固醇生成因子1(SF-1)是孤儿核受体家族中的一员，位于AMH近端启动子中，是AMH基因激活所必需的DNA结合元件。然而，对SF-1激活的特定启动子环境的要求以及AMH启动子中存在保守的顺式DNA结合元件表明SF-1是蛋白质-蛋白质和蛋白质-DNA复合体的成员。在这项研究中，我们证明了人类AMH近端启动子中典型的SOX结合位点可以结合转录因子SOX9，SOX9是一种与支持细胞分化和AMH表达密切相关的支持细胞因子。对COS-7细胞的转染研究表明，SOX9与SF-1在这一激活过程中具有协同作用。体外和体内的蛋白质结合研究表明，SOX9和SF-1分别通过SOX9的DNA结合区和SF-1的C末端直接相互作用。我们认为两个转录因子SOX9和SF-1都可能参与AMH基因的表达，部分原因是它们各自与AMH启动子结合，部分原因是它们相互作用的能力。因此，我们的工作确定SOX9是SF-1的相互作用伙伴，可能参与AMH在胚胎发育过程中的支持细胞特异性表达。
For proper male sexual differentiation, anti-Mullerian hormone (AMH) must be tightly regulated during embryonic development to promote regression of the Mullerian duct. However, the molecular mechanisms specifying the onset of AMH in male mammals are not yet clearly defined. A DNA-binding element for the steroidogenic Factor 1 (SF-1), a member of the orphan nuclear receptor family, located in the AMH proximal promoter has recently been characterized and demonstrated as being essential for AMH gene activation. However, the requirement for a specific promoter environment for SF-1 activation as well as the presence of conserved cis DNA-binding elements in the AMH promoter suggest that SF-1 is a member of a combinatorial protein-protein and protein-DNA complex. In this study, we demonstrate that the canonical SOX-binding site within the human AMH proximal promoter can bind the transcription factor SOX9, a Sertoli cell factor closely associated with Sertoli cell differentiation and AMH expression. Transfection studies with COS-7 cells revealed that SOX9 can cooperate with SF-1 in this activation process. In vitro and in vivo protein-binding studies indicate that SOX9 and SF-1 interact directly via the SOX9 DNA-binding domain and the SF-1 C-terminal region, respectively. We propose that the two transcription factors SOX9 and SF-1 could both be involved in the expression of the AMH gene, in part as a result of their respective binding to the AMH promoter and in part because of their ability to interact with each other. Our work thus identifies SOX9 as an interaction partner of SF-1 that could be involved in the Sertoli cell-specific expression of AMH during embryogenesis.