Loss of expression of GADD45 gamma, a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis.
The underlying molecular pathogenic mechanisms remain unknown in the majority of human pituitary tumors. GADD45 gamma 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 gamma gene is significantly different between normal human pituitary tissue and clinically nonfunctioning pituitary adenomas using cDNA-representational difference analysis. Although GADD45 gamma 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 gamma cDNA into the human pituitary tumor-derived cell line, PDFS, results in a dramatic decrease in cell growth by 88%. GADD45 gamma 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 gamma is a powerful growth suppressor controlling pituitary cell proliferation, and GADD45 gamma represents the first identified gene whose expression is lost in the majority of human pituitary tumors.
Zhang
Xun
X
Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Sun
Huiping
H
Danila
Daniel C
DC
Johnson
Stacey R
SR
Zhou
Yunli
Y
Swearingen
Brooke
B
Klibanski
Anne
A
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D000097642:GADD45 Proteins
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D000097642:GADD45 Proteins; C485654:GADD45G protein, human