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Submitted on July 28, 2005
Accepted on September 17, 2005
Laboratorio de Fisiología y Biología Molecular. Depto. de Fisiología, Biología Molecular y Celular, FCEN, Universidad de Buenos Aires, Buenos Aires, Argentina; Max-Planck Institute of Psychiatry, Kraepelinstr. 10, 80804 Munich, Germany; Hospital Santa Lucía, 1232 Buenos Aires, Argentina; Dept of Neurosurgery, Ospedale San Raffaele IRCCS, Milano, Italy; Dept of Neurosurgery, University of Gottingen Medical School, Robert-Kach-Str. 40, 37075 Gottingen, Germany; Members of the IFYBINE-Argentine National Research Council (CONICET); Affectis Pharmaceuticals, Munich, Germany
* To whom correspondence should be addressed. E-mail: earzt{at}fbmc.fcen.uba.ar.
The molecular mechanisms governing the pathogenesis of ACTH-secreting pituitary adenomas are still obscure. Furthermore, the pharmacological treatment of these tumors is limited. Here we report that BMP-4 is expressed in the corticotrophs of human normal adenohypophysis and its expression is reduced in corticotrophinomas obtained from Cushing's patients compared with the normal pituitary. BMP-4 treatment of AtT-20 mouse corticotrophinoma cells has an inhibitory effect on ACTH secretion and cell proliferation. AtT-20 cells stably transfected with a dominant negative form of the BMP-4 signal co-transducer Smad-4 or the BMP-4 inhibitor noggin have increased tumorigenicity in nude mice, showing that BMP-4 has an inhibitory role on corticotroph tumorigenesis in vivo. Since the activation of the retinoic acid receptor has an inhibitory action on Cushing's disease progression, we analyzed the putative interaction of these two pathways. Indeed, retinoic acid induces both BMP-4 transcription and expression and its antiproliferative action is blocked in Smad-4dn and noggin transfected Att-20 cells that do not respond to BMP-4. Therefore retinoic acid induces BMP-4, which participates in the antiproliferative effects of retinoic acid. This new mechanism is a potential target for therapeutic approaches for Cushing's disease.
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