TRANSFORMING-GROWTH-FACTOR-BETA, TRANSFORMING-GROWTH-FACTOR-BETA-RECEPTOR II, AND P27(KIP1) EXPRESSION IN NONTUMOROUS AND NEOPLASTIC HUMAN PITUITARIES

Transforming growth factor (TGF)-beta has been implicated in the regul ation of normal and neoplastic anterior pituitary cell function, TGF-b eta regulates the expression of various proteins, including p27(kip1) (p27), a cell cycle inhibitory protein. We examined TGF-beta, TGF-beta type II receptor (TGF-beta-RII), and p27 expression in normal pituita ries, pituitary adenomas, and carcinomas to analyze the possible roles of these proteins in pituitary tumorigenesis, Normal pituitary, pitui tary adenomas, and pituitary carcinomas all expressed TGF-beta and TGF -beta-RII immunoreactivity, Reverse transcription polymerase chain rea ction analysis showed TGF-beta 1, -beta 2, and -beta 3 isoforms and TG F-beta-RII in normal pituitaries and pituitary adenomas, Pituitary ade noma cells cultured for 7 days in defined media showed a biphasic resp onse to TGF-beta with significant inhibition of follicle-stimulating h ormone secretion at higher concentrations (10(-9) mol/L) and stimulati on of follicle-stimulating hormone secretion at lower concentrations ( 10(-13) mol/L) of TGF-beta 1 in gonadotroph adenomas, Immunohistochemi cal analysis for p27 protein expression showed the highest levels in n ontumorous pituitaries with decreased immunoreactivity in adenomas and carcinomas, When nontumorous pituitaries and various adenomas were an alyzed for p27 and specific hormone production, growth hormone, lutein izing hormone, and thyroid-stimulating hormone cells and tumors had th e highest percentages of cells expressing p27, whereas adrenocorticotr ophic hormone cells and tumors had the lowest percentages, Immunoblott ing analysis showed that adrenocorticotrophic hormone adenomas also ha d the lowest levels of p27 protein, Semiquantitative reverse transcrip tion polymerase chain reaction and Northern hybridization analysis did not show significant differences in p27 mRNA expression in the variou s types of adenomas or in nontumorous pituitaries, In situ hybridizati on for p27 mRNA showed similar distributions of the gene product in no ntumorous pituitaries, pituitary adenomas, and carcinomas, These resul ts indicate that TGF-beta and TGF-beta-RII are widely expressed in non tumorous pituitaries and in pituitary neoplasms and that TGF-beta 1 re gulates pituitary hormone secretion. The levels of the TGF-beta-regula ted protein p27 decreases in the progression of normal to neoplastic p ituitaries, In contrast, the mRNA levels of p27 remained relatively co nstant in nontumorous pituitaries, pituitary adenomas, and carcinomas, indicating that p27 protein levels in adenomas and carcinomas are reg ulated by translational and post-translational mechanisms.