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

in Journal of Molecular Endocrinology
Correspondence should be addressed to E Arzt: earzt@ibioba-mpsp-conicet.gov.ar

*(L Nieto and M Fuertes contributed equally to this work)

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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.

 

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    RA inhibitory action on ACTH secretion and Pomc transcription is increased by the BMP-4 signaling pathway. (A) AtT-20 cells were treated for 24 h with BMP-4, RA, or their combinations as indicated, under CRH (100 nM) treatment. ACTH was measured in the supernatants by radioimmunoassay, and the average of three wells per treatment and s.e.m. from one representative experiment of three with similar results are shown. **P < 0.01; ***P < 0.001; ANOVA with Bonferroni contrast. (B) AtT-20 cells were co-transfected with Pomc-LUC reporter vector (500 ng), RSV-β-gal construct (200 ng) and SMAD6 or SMAD7 expression vector (100 ng) or empty vector and treated with BMP-4, RA or their combination as indicated. After 24-h treatment, luciferase activity was measured and normalized. Values indicating the mean ± s.e.m. of luciferase to β-galactosidase ratio of one representative experiment of four with similar results are shown. *P < 0.05; ***P < 0.001; ANOVA with Bonferroni contrast. (C) pSMAD1/5 expression was studied by WB in AtT-20 cells treated with BMP-4, RA or their combination as indicated. (D) AtT-20 cells were co-transfected with RARE-LUC reporter vector (500 ng), RSV-β-gal construct (200 ng) and SMAD6 or SMAD7 expression vector (100 ng) or empty vector and treated with BMP-4, RA or their combination as indicated. After 24-h treatment, luciferase activity was measured and normalized. Values indicating the mean ± s.e.m. of luciferase-to-β-galactosidase ratio of one representative experiment of four with similar results are shown. ***P < 0.001; n.s, not significant; ANOVA with Bonferroni contrast. (E) AtT-20 cells were co-transfected with BMPRE-LUC reporter vector (500 ng) and RSV-β-gal construct (200 ng), and treated with BMP-4, RA or their combination as indicated. After 24-h treatment, luciferase activity was measured and normalized. Values indicating the mean ± s.e.m. of luciferase-to-β-galactosidase ratio of one representative experiment of three with similar results are shown. **P < 0.01; n.s, not significant; ANOVA with Bonferroni contrast. (F) AtT-20 cells or AtT-20 SMAD4-DN stable clones were co-transfected with Pomc-LUC reporter vector (500 ng) and RSV-β-gal construct (200 ng) and treated with BMP-4, RA or their combination as indicated. After 24-h treatment, luciferase activity was measured and normalized. Values indicating the mean ± s.e.m. of luciferase-to-β-galactosidase ratio of one representative experiment of three with similar results are shown. **P < 0.01; ***P < 0.001; ANOVA with Bonferroni contrast.

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    AtT-20 corticotroph cells express RA receptors, which interact with elements of the BMP-4 signaling pathway. (A) Retinoid and Rexinoid receptors (RAR and RXR) expression was studied by WB in AtT-20 cells and the specific band is indicated by an arrow. Cell extracts from HeLa (for RARA, RARG and RXRs) or HEK293T (for RARB) were used as positive controls. (B and C) AtT-20 cells were treated for 24 h with BMP-4, RA or their combination as indicated. Cell lysates were IP with anti-SMAD4 (1 µg) (B) or anti-SMAD1 (1 µg) (C) and analyzed by WB. M, mock. One representative of three independent experiments with similar results is shown.

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    RARE and BMPRE sites at the Pomc promoter. (A) Schematic representation of rat Pomc promoter (GenBank: X03171.1) in which we found by in silico analysis two consensus sequence, one for RA (RARE site, −63 to −68) and one for BMP (BMPRE site, −419 to −423). The scheme shows the distal (dotted), central (gray), proximal (lined) and minimal (white) promoter regions, and the different Pomc constructs used (complete promoter, with RARE site or with BMPRE site only, and mutated BMPRE site or RARE site). (B and C) AtT-20 cells were co-transfected with Pomc-LUC constructs (500 ng) and RSV-β-gal vector (200 ng), and treated with BMP-4, RA or their combination as indicated. After 24-h treatment, luciferase activity was measured and normalized. Values indicating the mean ± s.e.m. of luciferase-to-β-galactosidase ratio of one representative experiment of three with similar results are shown. n.s, not significant; *P < 0.05; **P < 0.01; ***P < 0.001; ANOVA with Bonferroni contrast. (D) EMSA of binding reactions using RARE sequence of the Pomc promoter as probe and AtT-20 cell nuclear extracts (NE) treated with BMP-4, RA or their combination as indicated. Binding complex is indicated by an arrow. Anti-SMAD4, anti-RARB and anti-RXRA antibodies (2 µg) were used to disrupt the binding complex; anti-actin antibody was used as control. Unlabeled probe was used as competitor to displace the formed complex. The experiment shown is representative for two independent experiments with similar results.

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    COUP-TFI hampers the formation of transcriptional complexes between elements of the BMP-4 signaling pathway and RA receptors. (A and B) AtT-20 cells were transfected with COUP-TFI expression vector or empty vector and treated for 24 h with BMP-4, RA or their combination as indicated. Cell lysates were IP with anti-SMAD4 (1 µg) (A) or anti-SMAD1 (1 µg) (B) and analyzed by WB. One representative of three independent experiments with similar results is shown. V, vehicle; B, 100 ng/mL BMP-4; R, 100 nM RA; BR, 100 ng/mL BMP-4 + 100 nM RA; M, mock. (C, D, E and F) AtT-20 cells were co-transfected with POMC-LUC (C) or RARE-LUC (D) or Pomc promoter with BMPRE deletion (E) or Pomc promoter with BMPRE mutation (F) reporter vector (500 ng), RSV-β-gal construct (200 ng) and COUP-TFI expression vector (400 ng) or empty vector and treated with BMP-4, RA or their combination as indicated. After 24-h treatment, luciferase activity was measured and normalized. Values indicating the mean ± s.e.m. of luciferase-to-β-galactosidase ratio of one representative experiment of three with similar results are shown. n.s, not significant; *P < 0.05; **P < 0.01; ***P < 0.001; ANOVA with Bonferroni contrast.

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    TOB1 disrupts the formation of transcriptional complexes between RA receptors and elements of the BMP-4 signaling. (A and B) AtT-20 cells were transfected with TOB1 expression vector or empty vector and treated for 24 h with BMP-4, RA or their combination as indicated. Cell lysates were IP with anti-SMAD4 (1 µg) (A) or anti-SMAD1 (1 µg) (B) and analyzed by WB. One representative of two independent experiments with similar results is shown. V, vehicle; B, 100 ng/mL BMP-4; R, 100 nM RA; BR, 100 ng/ml BMP-4 + 100 nM RA; M, mock. (C and D) AtT-20 cells were co-transfected with Pomc-LUC (C) or RARE-LUC (D) reporter vector (500 ng), RSV-β-gal construct (200 ng) and TOB1 expression vector (300 ng) or empty vector, and treated with BMP-4, RA or their combination as indicated. After 24-h treatment, luciferase activity was measured and normalized. Values indicating the mean ± s.e.m. of luciferase-to-β-galactosidase ratio of one representative experiment of three with similar results are shown. n.s, not significant; *P < 0.05; **P < 0.01; ***P < 0.001; ANOVA with Bonferroni contrast.

  • View in gallery

    RA and BMP-4 signaling pathways interaction in pituitary corticotroph cells. (A) Schematic representation of mouse Crh-r1 promoter (GenBank: 12921). In silico analysis displays one consensus sequence for RA (RARE site, white box) and four for BMP (BMPRE site, gray boxes). (B) AtT-20 cells or AtT-20 SMAD4-DN stable clones were co-transfected with Crh-r1-LUC reporter vector (500 ng) and RSV-β-gal construct (200 ng) and treated with BMP-4, RA or their combination as indicated. After 24-h treatment, luciferase activity was measured and normalized. Values indicating the mean ± s.e.m. of luciferase-to-β-galactosidase ratio of one representative experiment of three with similar results are shown. *P < 0.05; **P < 0.01; ***P < 0.001; ANOVA with Bonferroni contrast. (C) The proposed model of interaction between both RA and BMP-4 signaling pathways, in which the presence of the transcriptional complex formed by RA receptors and signal transducers SMADs on the RARE site triggers the inhibition of the transcriptional activity, while the presence of transcriptional modulators of both pathways, COUP-TFI for RA signaling and Tob1 for BMP-4 signaling, act to regulate and ameliorate the inhibitory effect of the interaction, and thus allowing Pomc transcription. Without ligands, these complexes have a constitutive binding probably without the cofactors induced by BMP-4 and RA that contribute to their potentiated action.

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