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Submitted on April 6, 2001
Accepted on January 8, 2003
1 Cedars-Sinai Research Institute-UCLA School of Medicine, Los Angeles, California
* To whom correspondence should be addressed. E-mail: melmed{at}csmc.edu.
Pituitary tumor transforming gene (PTTG) originally isolated from GH-secreting pituitary adenoma cells causes in vitro cell transformation, in vivo tumorigenesis, and induces bFGF. These functions require an intact C-terminal PXXP motif. PTTG1 is abundantly expressed in human pituitary tumors and plays a role in the early stages of experimental prolactinoma formation. We now determined direct effects of PTTG1 on hormonal phenotypes of functional pituitary tumor cells. Overexpression of PTTG1 C-terminus (amino acids 147-202) containing intact proline-proline-serine-proline (PXXP) motifs in rat PRL- and GH-secreting GH3 cells markedly abrogates PRL mRNA expression by 90% (P < 0.001) and hormone levels (P < 0.001) and PRL promoter activity (P < 0.01) compared with control vector cells or to a PTTG1 C-terminus mutant (P163A, S165Q, P166L, P170L, P172A, and P173L). Wild-type PTTG1 C-terminal transfectants formed smaller (P < 0.05) sc tumors in rats compared with control or mutated PTTG1 C-terminal transfectants. Estrogen (10 nM) treatment for 48 h partially restored PRL expression in stable wildtype PTTG1 C-terminal transfectants. These results indicate that targeting PTTG1-mediated signaling alters the hormonal phenotype in pituitary cells and disrupted PTTG1 action may be a potential subcellular therapeutic tool for repressing PRL hypersecretion.
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