Brand C, Cherradi N, Defaye G, Chinn A, Chambaz E M, Feige J J, Bailly S
Commissariat à l'Energie Atomique, Département de Biologie Moléculaire et Structurale, Biochìmìe des Régulations Cellulaires Endocrines, INSERM Unité 244, 17 rue des Martyrs, F-38054 Grenoble, France.
J Biol Chem. 1998 Mar 13;273(11):6410-6. doi: 10.1074/jbc.273.11.6410.
Transforming growth factor-betas (TGF-betas) constitute a family of dimeric proteins that affect growth and differentiation of many cell types. TGF-beta1 has also been proposed to be an autocrine regulator of adrenocortical steroidogenesis, acting mainly by decreasing the expression of cytochrome P450c17. Here, we demonstrate that TGF-beta1 has a second target in bovine adrenocortical cells, namely the steroidogenic acute regulatory protein (StAR). Indeed, supplying cells with steroid precursors revealed that TGF-beta1 inhibited two steps in the steroid synthesis pathway, one prior to pregnenolone production and another corresponding to P450c17. More specifically, TGF-beta1 inhibited pregnenolone production but neither the conversion of 25-hydroxycholesterol to pregnenolone nor P450scc activity. Thus, TGF-beta1 must decrease the cholesterol supply to P450scc. We therefore examined the effect of TGF-beta1 on the expression of StAR, a mitochondrial protein implicated in intramitochondrial cholesterol transport. TGF-beta1 decreased the steady state level of StAR mRNA in a time- and concentration-dependent manner. This inhibition occurs at the level of StAR transcription and depends on RNA and protein synthesis. It is likely that the TGF-beta1-induced decrease of StAR expression that we report here may be expanded to other steroidogenic cells in which a decrease of cholesterol accessibility to P450scc by TGF-beta1 has been hypothesized.
转化生长因子-β（TGF-β）构成一类二聚体蛋白家族，可影响多种细胞类型的生长和分化。TGF-β1也被认为是肾上腺皮质类固醇生成的自分泌调节因子，主要通过降低细胞色素P450c17的表达发挥作用。在此，我们证明TGF-β1在牛肾上腺皮质细胞中有第二个作用靶点，即类固醇生成急性调节蛋白（StAR）。事实上，为细胞提供类固醇前体表明，TGF-β1抑制类固醇合成途径中的两个步骤，一个在孕烯醇酮生成之前，另一个对应于P450c17。更具体地说，TGF-β1抑制孕烯醇酮的生成，但既不抑制25-羟胆固醇向孕烯醇酮的转化，也不抑制P450scc的活性。因此，TGF-β1必定会减少向P450scc的胆固醇供应。我们因此研究了TGF-β1对StAR表达的影响，StAR是一种参与线粒体内胆固醇转运的线粒体蛋白。TGF-β1以时间和浓度依赖的方式降低StAR mRNA的稳态水平。这种抑制发生在StAR转录水平，并且依赖于RNA和蛋白质合成。我们在此报道的TGF-β1诱导的StAR表达降低很可能会扩展到其他类固醇生成细胞，在这些细胞中，已推测TGF-β1会降低胆固醇对P450scc的可及性。
