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Loss of Expression of GADD45, a Growth Inhibitory Gene, in Human Pituitary Adenomas: Implications for Tumorigenesis

Neuroendocrine Unit (X.Z., H.S., D.C.D., S.R.J., Y.Z., A.K.) and Neurosurgical Service (B.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Anne Klibanski, M.D., Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BUL 457B, Boston, Massachusetts 02114. E-mail: . aklibanski{at}partners.org

Abstract

The underlying molecular pathogenic mechanisms remain unknown in the majority of human pituitary tumors. GADD45 is a member of a growth arrest and DNA damage-inducible gene family that functions in the negative regulation of cell growth. We have found that the mRNA expression of the GADD45 gene is significantly different between normal human pituitary tissue and clinically nonfunctioning pituitary adenomas using cDNA-representational difference analysis. Although GADD45 mRNA was found in normal human pituitary tissue, it was detectable in only 1 of 18 clinically nonfunctioning pituitary tumors by RT-PCR. Furthermore, this gene was not expressed in the majority of GH- or PRL-secreting pituitary tumors (6 of 8 and 7 of 10, respectively). In colony formation assays, transfection of human GADD45 cDNA into the human pituitary tumor-derived cell line, PDFS, results in a dramatic decrease in cell growth by 88%. GADD45 also reduces colony formation in other pituitary tumor-derived cell lines, AtT20 and GH4, by approximately 60% and 50%, respectively, confirming its function in controlling cell proliferation in the pituitary. These data indicate that GADD45 is a powerful growth suppressor controlling pituitary cell proliferation, and GADD45 represents the first identified gene whose expression is lost in the majority of human pituitary tumors.

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