Crosstalk of BMP-4 and RA signaling pathways on POMC gene regulation in corticotrophs

Journal of Molecular Endocrinology
Leandro NietoEduardo Arzt

Abstract

Retinoic acid (RA), an active metabolite of Vitamin A, and Bone Morphogenetic Protein 4 (BMP-4) pathways control the transcription of Proopiomelanocortin (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 (RARβ, RXRα and RXRγ) 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 molecule...Continue Reading

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