Tau K R, Hefferan T E, Waters K M, Robinson J A, Subramaniam M, Riggs B L, Spelsberg T C
Department of Biochemistry and Molecular Biology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
Endocrinology. 1998 Mar;139(3):1346-53. doi: 10.1210/endo.139.3.5830.
This laboratory reported the identification and characterization of a unique three zinc finger, transcription factor-like, transforming growth factor-beta 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 17beta-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.
本实验室报告了一种独特的三锌指转录因子样转化生长因子-β诱导早期基因（TIEG）的鉴定与特性（见参考文献35）。TIEG的表达已显示出具有组织和细胞类型特异性，可被特定生长因子增强，并随着乳腺癌进展阶段而降低。最近涉及胰腺癌细胞中TIEG过表达的研究表明，TIEG表达抑制DNA合成，类似于肿瘤抑制样基因，并在细胞凋亡中起作用（见参考文献37）。本文描述了17β-雌二醇（E2）在雌激素受体（ER）阳性的人胎儿成骨细胞（hFOB/ER）中快速但短暂地诱导TIEG稳态信使核糖核酸（mRNA）水平。这种快速诱导显示为ER和类固醇剂量依赖性，但与蛋白质合成无关。在骨骼代谢中发生的E2与甲状旁腺激素（PTH）之间的拮抗作用，被证明与TIEG mRNA表达迅速一致。扫描共聚焦显微镜（使用偏振激光免疫荧光）显示，TIEG蛋白定位于hFOB/ER细胞的细胞核中，E2处理后其水平迅速增加。E2诱导的TIEG表达快速增加之后，hFOB/ER细胞中出现E2诱导的DNA合成抑制。抗雌激素不仅阻断TIEG mRNA水平的诱导，还阻断细胞增殖的抑制。最后，与未转染细胞相比，稳定转染TIEG表达载体的hFOB细胞显示出DNA合成/细胞增殖明显减少。这些结果支持了TIEG是人类成骨细胞中E2的早期反应调节基因且抑制DNA合成这一发现。据推测，TIEG可能在E2抑制细胞增殖的信号通路中起作用。
