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Estrogen Regulation of a Transforming Growth Factor-ß Inducible Early Gene That Inhibits Deoxyribonucleic Acid Synthesis in Human Osteoblasts¹

Department of Biochemistry and Molecular Biology (K.R.T., T.E.H., K.M.W., J.A.R., M.S., T.C.S.), Department of Internal Medicine (B.L.R.), Division of Endocrinology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Thomas C. Spelsberg, Department of Biochemistry and Molecular Biology, Division of Endocrinology, Mayo Clinic and Mayo Foundation, Guggenheim Building, Room 1601A, Rochester, Minnesota 55905. E-mail: Spelsberg.Thomas{at}mayo.edu

This laboratory reported the identification and characterization of a unique three zinc finger, transcription factor-like, transforming growth factor-ß inducible early gene (TIEG) (see Ref. 35). TIEG expression has been shown to be tissue- and cell type specific, enhanced by specific growth factors, and to decrease with advancing stages of breast cancer. Recent studies involving TIEG overexpression in pancreatic carcinoma cells indicate that TIEG expression inhibits DNA synthesis, similar to a tumor suppressor-like gene, and plays a role in apoptosis (see Ref. 37). This paper describes the rapid, but transient, induction of TIEG steady-state messenger RNA (mRNA) levels by 17ß-estradiol (E₂) in estrogen receptor (ER)-positive, human fetal osteoblastic (hFOB/ER) cells. This rapid induction is shown to be ER- and steroid dose-dependent but protein synthesis independent. An antagonism between E₂ and PTH, which occurs in skeletal metabolism, is shown to concur rapidly with TIEG mRNA expression. Scanning confocal microscopy (using polarized, laser-based immunofluorescence) shows that TIEG protein is localized in the nucleus of hFOB/ER cells, with the levels rapidly increasing after E₂ treatment. The rapid E₂-induced increase in TIEG expression is followed by an E₂-induced inhibition of DNA synthesis in the hFOB/ER cells. Antiestrogens block not only the induction of TIEG mRNA levels but also the inhibition of cell proliferation. Lastly, hFOB cells, stably transfected with a TIEG expression vector, display markedly reduced DNA synthesis/cell proliferation, compared with nontransfected cells. These results support the finding that TIEG is an early responding regulatory gene for E₂ in human osteoblast cells that inhibits DNA synthesis. It is speculated that TIEG may play a role in the signaling pathway for E₂ in inhibiting cell proliferation.

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