ESTROGEN REGULATION OF A TRANSFORMING-GROWTH-FACTOR-BETA INDUCIBLE EARLY GENE THAT INHIBITS DEOXYRIBONUCLEIC-ACID SYNTHESIS IN HUMAN OSTEOBLASTS

This laboratory reported the identification and characterization of a unique three zinc finger, transcription factor-like, transforming grow th factor-beta inducible early gene (TIEG) (see Ref. 35). TIEG express ion has been shown to be tissue-and cell type specific, enhanced by sp ecific growth factors, and to decrease with advancing stages of breast cancer. Recent studies involving TIEG overexpression in pancreatic ca rcinoma cells indicate that TIEG expression inhibits DNA synthesis, si milar 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 17 beta-estradiol (E-2) in estrogen receptor (ER)-positive, human fetal osteoblastic (hF OB/ER) cells. This rapid induction is shown to be ER- and steroid dose -dependent but protein synthesis independent. An antagonism between E- 2 and PTH, which occurs in skeletal metabolism, is shown to concur rap idly with TIEG mRNA expression. Scanning confocal microscopy (using po larized, laser-based immunofluorescence) shows that TIEG protein is lo calized in the nucleus of hFOB/ER cells, with the levels rapidly incre asing after E-2 treatment. The rapid E-2-induced increase in TIEG expr ession is followed by an E-2-induced inhibition of DNA synthesis in th e hFOB/ER cells. Antiestrogens block not only the induction of TIEG mR NA levels but also the inhibition of cell proliferation. Lastly, hFOB cells, stably transfected with a TIEG expression vector, display marke dly reduced DNA synthesis/cell proliferation, compared with nontransfe cted cells. These results support the finding that TIEG is an early re sponding regulatory gene for E-2 in human osteoblast cells that inhibi ts DNA synthesis. It is speculated that TIEG may play a role in the si gnaling pathway for E-2 in inhibiting cell proliferation.