Crawford P A, Polish J A, Ganpule G, Sadovsky Y
Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Mol Endocrinol. 1997 Oct;11(11):1626-35. doi: 10.1210/mend.11.11.9970.
The orphan receptor steroidogenic factor 1 (SF-1) plays a central role in development and differentiation of the adrenal gland and gonads. It also regulates the expression of several pivotal steroidogenic enzymes and other proteins that are essential for reproductive function. Its mechanism of target gene activation that directs these intricate processes has not been previously established. We demonstrate here that the activation function-2 (AF-2) activation hexamer (AF-2-AH) of SF-1, located within its carboxy-terminal region, is required for reporter gene activation by SF-1, as well as for SF-1-mediated induction of a steroidogenic phenotype in embryonic stem cells. We further demonstrate that SF-1's AF-2-AH is not sufficient for gene activation, requiring an additional, proximally located domain of SF-1, positioned between residues 187-245. Correspondingly, we show that the coactivator SRC-1 potentiates the activity of SF-1 and that the interaction between SF-1 and SRC-1 requires both AF-2-AH and the proximal activation domain. We conclude that SF-1 harbors at least two activation domains within its carboxy terminus and that both are required for its transcriptional activation function and for direct interaction with SRC-1. It is likely that SRC-1 plays a key role in gene regulation by SF-1.
孤儿受体类固醇生成因子1（SF-1）在肾上腺和性腺的发育与分化过程中发挥着核心作用。它还调控着几种关键的类固醇生成酶以及其他对生殖功能至关重要的蛋白质的表达。此前尚未明确其指导这些复杂过程的靶基因激活机制。我们在此证明，位于SF-1羧基末端区域的激活功能-2（AF-2）激活六聚体（AF-2-AH），对于SF-1激活报告基因以及在胚胎干细胞中介导SF-1诱导类固醇生成表型而言是必需的。我们进一步证明，SF-1的AF-2-AH不足以实现基因激活，还需要SF-1位于187 - 245位残基之间的一个额外的近端结构域。相应地，我们表明共激活因子SRC-1增强了SF-1的活性，并且SF-1与SRC-1之间的相互作用既需要AF-2-AH也需要近端激活结构域。我们得出结论，SF-1在其羧基末端至少含有两个激活结构域，这两个结构域对于其转录激活功能以及与SRC-1的直接相互作用都是必需的。SRC-1很可能在SF-1对基因的调控中发挥关键作用。
