Transforming growth factor-β, transforming growth factor-β receptor II, and p27(Kip1) expression in nontumorous and neoplastic human pituitaries

Long Jin, Xiang Qian, Elzbieta Kulig, Naoko Sanno, Bernd W. Scheithauer, Kaiman Kovacs, William F. Young, Ricardo V. Lloyd

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130 Scopus citations

Abstract

Transforming growth factor (TGF)-β has been implicated in the regulation of normal and neoplastic anterior pituitary cell function. TGF-β regulates the expression of various proteins, including p27(Kip1) (p27), a cell cycle inhibitory protein. We examined TGF-β, TGF-β type II receptor (TGF-β-RII), and p27 expression in normal pituitaries, pituitary adenomas, and carcinomas to analyze the possible roles of these proteins in pituitary tumorigenesis. Normal pituitary, pituitary adenomas, and pituitary carcinomas all expressed TGF-β and TGF-β-RII immunoreactivity. Reverse transcription polymerase chain reaction analysis showed TGF-β1, -β2, and -β3 isoforms and TGF-β-RII in normal pituitaries and pituitary adenomas. Pituitary adenoma cells cultured for 7 days in defined media showed a biphasic response to TGF-β with significant inhibition of follicle-stimulating hormone secretion at higher concentrations (10-9 mol/L) and stimulation of follicle-stimulating hormone secretion at lower concentrations (10-13 mol/L) of TGF-β1 in gonadotroph adenomas. Immunohistochemical analysis for p27 protein expression showed the highest levels in nontumorous pituitaries with decreased immunoreactivity in adenomas and carcinomas. When nontumorous pituitaries and various adenomas were analyzed for p27 and specific hormone production, growth hormone, luteinizing hormone, and thyroid-stimulating hormone cells and tumors had the highest percentages of cells expressing p27, whereas adrenocorticotrophic hormone cells and tumors had the lowest percentages. Immunoblotting analysis showed that adrenocorticotrophic hormone adenomas also had the lowest levels of p27 protein. Semiquantitative reverse transcription polymerase chain reaction and Northern hybridization analysis did not show significant differences in p27 mRNA expression in the various types of adenomas or in nontumorous pituitaries. In situ hybridization for p27 mRNA showed similar distributions of the gene product in nontumorous pituitaries, pituitary adenomas, and carcinomas. These results indicate that TGF-β and TGF-β-RII are widely expressed in nontumorous pituitaries and in pituitary neoplasms and that TGF-β1 regulates pituitary hormone secretion. The levels of the TGF-β-regulated protein p27 decreases in the progression of normal to neoplastic pituitaries. In contrast, the mRNA levels of p27 remained relatively constant in nontumorous pituitaries, pituitary adenomas, and carcinomas, indicating that p27 protein levels in adenomas and carcinomas are regulated by translational and post-translational mechanisms.

Original languageEnglish (US)
Pages (from-to)509-519
Number of pages11
JournalAmerican Journal of Pathology
Volume151
Issue number2
StatePublished - Aug 19 1997

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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