Gizang-Ginsberg E, Ziff E B
Howard Hughes Medical Institute, Department of Biochemistry, New York University Medical Center, New York 10016.
Mol Endocrinol. 1994 Feb;8(2):249-62. doi: 10.1210/mend.8.2.7909583.
Nerve growth factor induces the neuronal-like differentiation of PC12 cells, and epidermal growth factor promotes PC12 viability and is weakly mitogenic. Despite these differences, both growth factors induce indistinguishable patterns of transient delayed transcription of the tyrosine hydroxylase (TH) gene and the expression of proteins encoded by Fos gene family members. Thus, TH expression is sensitive to signaling pathways common to these two growth factors. We show that c-fos and fosB successively occupy an AP-1 site-like element of the TH promoter after nerve growth factor treatment. Furthermore, under conditions of transient transfection, Fos family proteins may synergize with c-jun to transrepress TH gene transcription through the TH-fat-specific element. We show that the target of repression is the AP-1 site-like element that lies within the TH-fat-specific element. We demonstrate that this site is also a major positive acting site for TH control. These results suggest a model in which the long term effect of c-fos family protein expression is to limit the expression of the TH gene. We consider the novel properties of this element in providing temporal and cell type-specific regulation of TH transcription.
神经生长因子诱导PC12细胞向神经元样分化，而表皮生长因子促进PC12细胞的活力且有较弱的促有丝分裂作用。尽管存在这些差异，但这两种生长因子均能诱导酪氨酸羟化酶（TH）基因出现难以区分的短暂延迟转录模式以及Fos基因家族成员所编码蛋白质的表达。因此，TH的表达对这两种生长因子共有的信号通路敏感。我们发现，神经生长因子处理后，c-fos和fosB先后占据TH启动子的一个类AP-1位点元件。此外，在瞬时转染条件下，Fos家族蛋白可能与c-jun协同作用，通过TH-脂肪特异性元件反式抑制TH基因转录。我们发现抑制的靶点是位于TH-脂肪特异性元件内的类AP-1位点元件。我们证明该位点也是TH调控的一个主要正向作用位点。这些结果提示了一个模型，其中c-fos家族蛋白表达的长期效应是限制TH基因的表达。我们考虑了该元件在提供TH转录的时间和细胞类型特异性调控方面的新特性。
