Mechanisms of the Functional Interaction of Retinoic Acid and BMP-4 in Corticotrophinomas

ARZT, E; FUERTES, M; NIETO, LE

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias LXII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2017

SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC)

Cushing?s disease is an endocrine disorder due to a pituitary corticotrophinoma.We demonstrated in dogs the remission after administrationof Retinoic Acid (RA). Bone Morphogenetic Protein 4(BMP-4) also stops the tumoral progression. Our aim is to establishwhether there is a common thread between the signaling pathwaysof RA and BMP-4. Using the AtT-20 mouse tumor corticotroph cellline, we first confirmed the expression pattern of different type ofreceptors for RA (RXRα, β and γ ; RARβ and γ). By coimmunoprecipitationwe observed the interaction of RXRα, RXRγ and RARβ with Smad1 and Smad4 proteins, key components in the BMP-4signaling, under RA or BMP-4 stimuli for 24h. The transfection withan expression vector for COUP-TFI produced a reduction in the conformationof these complexes. COUP-TFI blocked from 40-80% to10% the inhibitory action of RA (100 nM) and the potentiation of theinhibition by BMP-4 (100 ng/ml) on the POMC-Luc promoter. We observedthat with a POMC-Luc containing both responding elements,RARE and BMPRE, the inhibitory effect of the co-treatment is maximum,while with only RARE, RA inhibited and a potentiation of thisinhibitory effect was still exerted by the co-treatment with BMP-4.A point mutation at the BMPRE shows that although the promoterdoes not respond to BMP-4 it still has the co-potentiation action withRA, indicating that BMP-4 does not need the BMPRE site (the mainresponding element to BMP-4) to potentiate the inhibitory action ofRA, that occurs at the RARE site. RA and BMP-4 form signalingcomplexes that interact at the transcriptional level, resulting in a potentialtarget to treat this disorder.Supported by ANPCyT, CONICET, UBA and FOCEM (COF 03/11).