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

: 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 molecules that participate in the control of corticotroph gene expression contribute to define more precise targets for the treatment of corticotrophinomas.