1. [New mechanisms involved in the pathogenesis of pituitary adenomas].
- Author
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Giacomini D, Páez-Pereda M, Refojo D, Carbia Nagashima A, Chervin A, Goldberg V, and Arzt E
- Subjects
- Animals, Bone Morphogenetic Protein 4, Bone Morphogenetic Proteins metabolism, Cell Division, DNA-Binding Proteins metabolism, Humans, Mice, Mice, Nude, Pituitary Neoplasms metabolism, Prolactinoma metabolism, Proto-Oncogene Proteins c-myc metabolism, Signal Transduction, Smad4 Protein, Trans-Activators metabolism, Bone Morphogenetic Proteins physiology, Pituitary Neoplasms genetics, Prolactinoma genetics
- Abstract
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.
- Published
- 2003