Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
División Endocrinología, Hospital General de Agudos 'Carlos G. Durand', Buenos Aires, Argentina.
J Mol Endocrinol. 2019 Oct;63(3):161-174. doi: 10.1530/JME-19-0059.
Retinoic acid (RA), an active metabolite of Vitamin A, and bone morphogenetic protein 4 (BMP-4) pathways control the transcription of pro-opiomelanocortin (Pomc), the precursor of ACTH. We describe a novel mechanism by which RA and BMP-4 act together in the context of pituitary corticotroph tumoral cells to regulate Pomc transcription. BMP-4 and RA exert a potentiated inhibition on Pomc gene expression. This potentiation of the inhibitory action on Pomc transcription was blocked by the inhibitory SMADs of the BMP-4 pathway (SMAD6 and SMAD7), a negative regulator of BMP-4 signaling (TOB1) and a blocker of RA pathway (COUP-TFI). AtT-20 corticotrophinoma cells express RA receptors (RARB, RXRA and RXRG) which associate with factors of BMP-4 (SMAD4 and SMAD1) signaling cascade in transcriptional complexes that block Pomc transcription. COUP-TFI and TOB1 disrupt these complexes. Deletions and mutations of the Pomc promoter and a specific DNA-binding assay show that the complexes bind to the RARE site in the Pomc promoter. The enhanced inhibitory interaction between RA and BMP-4 pathways occurs also in another relevant corticotroph gene promoter, the corticotropin-releasing hormone receptor 1 (Crh-r1). The understanding of the molecules that participate in the control of corticotroph gene expression contribute to define more precise targets for the treatment of corticotrophinomas.
视黄酸（RA），维生素 A 的一种活性代谢物，和骨形态发生蛋白 4（BMP-4）途径控制着促肾上腺皮质激素释放激素（ACTH）前体——促黑激素原（Pomc）的转录。我们描述了一个新的机制，即在垂体促肾上腺皮质细胞瘤中，RA 和 BMP-4 共同作用来调节 Pomc 转录。BMP-4 和 RA 对 Pomc 基因表达有协同抑制作用。这种对 Pomc 转录抑制作用的增强被 BMP-4 途径的抑制性 SMAD（SMAD6 和 SMAD7）、BMP-4 信号的负调节剂（TOB1）和 RA 途径的阻断剂（COUP-TFI）阻断。AtT-20 促肾上腺皮质细胞瘤表达 RA 受体（RARB、RXRA 和 RXRG），它们与 BMP-4（SMAD4 和 SMAD1）信号级联中的因子结合，形成转录复合物，从而阻断 Pomc 转录。COUP-TFI 和 TOB1 破坏这些复合物。Pomc 启动子的缺失和突变以及特定的 DNA 结合测定表明，这些复合物结合到 Pomc 启动子中的 RARE 位点。RA 和 BMP-4 途径之间的增强的抑制性相互作用也发生在另一个相关的促肾上腺皮质激素基因启动子——促肾上腺皮质激素释放激素受体 1（Crh-r1）上。参与控制促肾上腺皮质激素基因表达的分子的理解有助于确定更精确的治疗促肾上腺皮质激素瘤的靶点。
