Human pituitary tumor-transforming gene (PTTG1) motif suppresses prolactin expression.
Pituitary tumor-transforming gene (PTTG) originally isolated from GH-secreting pituitary adenoma cells causes in vitro cell transformation, in vivo tumorigenesis, and induces basic fibroblast growth factor. These functions require an intact C-terminal proline-proline-serine-proline 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 motifs in rat prolactin (PRL)- and GH-secreting GH3 cells markedly abrogates PRL mRNA expression by more than 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 wild-type 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.
Horwitz
Gregory A
GA
Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 2015, Los Angeles, California 90048, USA.
Miklovsky
Irina
I
Heaney
Anthony P
AP
Ren
Song-Guang
SG
Melmed
Shlomo
S
D020816:Amino Acid Motifs; D000818:Animals; D015197:Carcinogenicity Tests; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D034285:Dynamin II / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism; D006728:Hormones / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism; D011388:Prolactin / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D064249:Securin; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D006728:Hormones; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human; D004958:Estradiol; D011388:Prolactin; D013006:Growth Hormone; D034285:Dynamin II