Target genes of RORα which controls postnatal development of cerebeller Purkinje cells

我们分析了Pcp-2、saposin原和5-脂氧合酶三个在浦肯野细胞中表达的基因的转录调控机制，这三个基因都含有RORα反应元件（RORE）。不含糖皮质激素反应元件的Pcp-2基因的RORα依赖性转录被糖皮质激素受体（GR）抑制。相反，RORα抑制MMTV启动子的GR依赖性转录。GR的N端和RORα的C端分别定位了转录拮抗作用所必需的区域。由于RORα和GR之间没有直接的相互作用，推测RORα和GR之间存在一种新的共同的转录拮抗介质：Prosaposin基因（pSAP）中含有一个RORE，它能与RORα有效结合。在P19和HeLa细胞中，RORα激活与pSAP基因RORE连接的tk基因启动子的转录，但对pSAP基因的转录无激活作用。与此相反，虽然GRE连接到pSAP基因不能激活其在P19中的转录，但它激活了HeLa细胞中的转录。这些结果表明，核受体的转录激活依赖于启动子的类型和细胞类型。由于真核基因启动子结构的多样性，在启动子上形成的基础转录复合体可能各不相同。RORα抑制5-脂氧合酶（5-lipoxygenase，5-LO）基因的转录。我们最近观察到，转录抑制是由于抑制了EGFR 1的功能，而EGFR 1是该基因的反式激活因子。

We analyzed regulatory mechanisms of transcription of three genes, Pcp-2, prosaposin and 5-lipoxygenase genes, which are expressed in the Purkinje cells and contain a RORα-responsive elemenet (RORE). RORα-dependent transcription of the Pcp-2 gene which does not contain a glucocorticoid responsive element was shown to be repressed by glucocorticoid receptor (GR). Reciprocally, GR-dependent transcription of MMTV promoter was repressed by RORα. Regions essential for the transcriptional antagonism was mapped to the N-terminus of GR and the C-terminus of RORα, respectively. Since RORα and GR did not directly interact each other, it was suggested that a novel mediator common for RORα and GR confers the transcriptional antagonism between them.Prosaposin gene (pSAP) contains a RORE which is efficiently bound with RORα. Although RORα activated transcription of the tk gene promoter linked with the RORE of pSAP gene, it failed to activate transcription of pSAP gene both in P19 and HeLa cells. In contrast, although GRE linked to pSAP gene failed to activate its transcription in P19, it activated the transcription in HeLa cells. These results indicated that transcriptional activation by nuclear receptors is dependent both on type of promoter and cell-type. Since promoters of eukaryptic genes show a structural variety, basal transcriptional complex formed on the promoter might differ from one to another. Nuclear receptor bound with its cognate responsive element interact differently to the basal transcription complex.Transcription of 5-lipoxygenase (5-LO) gene has been demonstrated to be repressed by RORα. We recently observed that the transcriptional repression results from suppression of EGR1 function which actc as a transactivator of this gene.