[New mechanisms involved in the pathogenesis of pituitary adenomas].
We studied Smad-4dn tumors generated from lactosomatotrophic GH3 cells stably transfected with a dominant negative form of Smad-4 (a bone morphogenetic protein-4, BMP-4, signal co-transducer) which had reduced tumorigenicity in nude mice, but had showed a late increase in tumor size. We found that they had lost in vivo the expression of Smad-4dn and had recovered c-Myc expression. In accordance, BMP-4 is overexpressed and stimulates the expression of c-Myc in human prolactinomas, but not in other human pituitary adenomas or normal pituitary. In addition ICI 182,780 inhibited BMP-4 stimulated c-Myc expression and BMP-4 and 17 beta-estradiol in combination had an additive effect on GH3 cell proliferation. Their action was inhibited by blocking BMP-4 with ICI 182,780 or 17 beta-estradiol with Smad-4dn. Furthermore, co-immunoprecipitation studies demonstrate that Smad-4 physically interacts with the ER alpha/ER beta. We show for the first time the role of BMP-4 in prolactinoma pathogenesis, involving a functional cross-talk BMP-4/E2.
Giacomini
Damiana
D
Departamento de Fisiologia, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
Páez-Pereda
Marcelo
M
Refojo
Damián
D
Carbia Nagashima
Alberto
A
Chervin
Alberto
A
Goldberg
Victoria
V
Arzt
Eduardo
E
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism; D015175:Prolactinoma / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism
C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators