GROWTH HORMONE SIGNALING TO THE NUCLEUS

生长激素向细胞核发出信号

• 批准号: 6380767
• 负责人: Jessica Schwartz
• 金额: $ 26.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6380767
• 关键词: acylation; biological signal transduction; cell nucleus; chromatin; enhancer binding protein; fos protein; hormone regulation /control mechanism; phosphorylation; somatotropin; tissue /cell culture; transcription factor; transfection

Growth is associated with complex genetic programs involving changes in the expression of many genes. Growth hormone (GH), a key regulator of normal growth, elicits changes in gene expression. In examining the mechanisms by which GH regulates gene transcription using c-fos as a model, we proposed that GH regulated multiple DNA sequences in c fos, and have now identified four: the Sis-Inducible Element (SIE) which binds Signal Transducers and Activators of Transcription (Stats) 1 and 3 in response to GH, the Serum Response Element (SRE) which requires Serum Response Factor (SRF) and Elk-1 to mediate GH- promoted transcription, an AP-1 site which can bind c-Fos and c- Jun; and a CCAAT/Enhancer Binding Protein (C/EBP) site which binds C/EBPbeta and delta. By analyzing regulation by GH of the transcription factors associated with these complexes, we have so far identified three distinct signalling pathways between the GH receptor (GHR) and the nucleus, mediated by Stats by Mitogen Activated Protein Kinases (MAPKs) and by phosphatidyl inositol 3' kinase (PI3K). The present proposal takes these findings as a point of departure to investigate the hypothesis that GH- regulated transcription involves formation of higher order transcription factor complexes and related chromatin remodelling. It is proposed to examine how the transcription factors on GH- regulated genes are coordinated into higher order complexes, and how co-activators and co-repressors participate in such complexes to bring about chromatin remodelling that contributes to transcriptional activation in response to GH. The first part of this proposal delineates the regulation and importance of the phosphorylation state of C/EBPbeta in GH-regulated transcription of c fos. C/EBPbeta is particularly informative because it interacts with many transcription factors and co-activators. Thus, C/EBPbeta provides a starting point for identifying higher order complexes in GH-regulated c-fos expression. Since Stat 5 participates in the regulation of several GH-regulated genes, some of which contain C/EBPbeta binding sites, the participation of Stat 5 in higher order transcription factor complexes regulated by GH will be examined. The assembly of such higher order complexes is likely to involve co-activator and/or co- repressor molecules which can interact with many of the individual transcription factors which GH regulates. Participation of co-activators and co-repressors and the resultant chromatin remodelling in GH-regulated transcription complexes will be examined. The proposed studies will provide critical information on mechanisms for GH-regulated gene transcription, for specificity in assembly of transcription complexes in response to GH on particular genes, and on coordinated regulation of gene expression applicable to multiple genes. By adding to our understanding of fundamental mechanisms for regulation of normal growth, they provide a basis for understanding aberrant cellular growth, as in cancer, and for design of rational therapies toward growth control.

生长与复杂的遗传程序有关，涉及许多基因表达的变化。 生长激素（GH）是正常生长的关键调节因子，可引起基因表达的变化。 在使用c-fos作为模型研究GH调节基因转录的机制时，我们提出GH调节c-fos中的多个DNA序列，现在已经确定了四个：Sis诱导元件（SIE），其响应于GH而结合信号转导子和转录激活子（Stats）1和3，血清应答元件（SRE），其需要血清应答因子（SRF）和Elk-1来介导GH促进的转录，AP-1位点，其可以结合c-Fos和c-Jun;和结合C/EBP β和δ的CCAAT/增强子结合蛋白（C/EBP）位点。 通过分析GH对与这些复合物相关的转录因子的调节，我们已经确定了GH受体（GHR）和细胞核之间的三种不同的信号传导途径，它们由Stats、促分裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3'激酶（PI 3 K）介导。 目前的建议，以这些发现为出发点，调查的假设，生长激素调节的转录涉及形成更高级别的转录因子复合物和相关的染色质重塑。建议检查GH调节基因上的转录因子如何协调成更高级的复合物，以及共激活子和共阻遏子如何参与这种复合物以引起染色质重塑，从而有助于响应GH的转录激活。 本提案的第一部分描述了C/EBPbeta磷酸化状态在GH调节的c fos转录中的调节和重要性。 C/EBP β是特别有用的，因为它与许多转录因子和共激活因子相互作用。因此，C/EBP β为鉴定GH调节的c-fos表达中的高阶复合物提供了一个起点。 由于Stat 5参与了几个GH调节基因的调节，其中一些含有C/EBP β结合位点，因此将检查Stat 5参与GH调节的高阶转录因子复合物。 这种更高级复合物的组装可能涉及共激活子和/或共阻遏子分子，其可以与GH调节的许多单个转录因子相互作用。将检查共激活子和共抑制子的参与以及由此产生的GH调节的转录复合物中的染色质重塑。 拟议的研究将提供关键信息GH调节基因转录的机制，在特定基因上的GH响应的转录复合物的组装的特异性，和适用于多个基因的基因表达的协调调节。 通过增加我们对正常生长调节的基本机制的理解，它们为理解异常细胞生长（如癌症）和设计合理的生长控制疗法提供了基础。