INTERPLAY OF E PROTEINS AND CYCLIN D1 DEPENDENT KINASES

E 蛋白和细胞周期 D1 依赖性激酶的相互作用

• 批准号: 2700717
• 负责人: DONALD STAVE KOHTZ
• 金额: $ 19.5万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2700717
• 关键词: B lymphocyte; cell cycle; cell differentiation; cell line; cell proliferation; chromosome translocation; cyclins; enzyme mechanism; gene expression; genetic transcription; human tissue; laboratory mouse; lymphoma; myoblasts; protein kinase; tissue /cell culture

For the effects on cell cycle progression or gene expression associated with individual cyclin types to be manifested, specific phosphorylation of selected substrates must occur. However, the mechanism of substrate selection and phosphoryiation by cyclin- dependent kinase complexes is not well understood. The E proteins (such as the products of the E2A gene) form homodimers and heterodimers with other bHLH proteins that are important in reguiating tissue-speccic gene expression. We have shown that activtion of transcription by certain E protein heterodimers is inhibited by cyclin D-1 dependent kinases. We have evidence that inhibition of myogenic BHLH regulators by cyclin dD1-dependent kinases is mediated by E protein dependent kase sites. Studies are proposed to investigate the mechanism of inhibition, and to determine how cyclin D1-dependent lltase complexes specifically recognize E protein heterodimers and homodimers as substrates. Independent of their function as transcriptional actors, expression of the E2A gene products can induce growth arrest in certin cell lines. We will investigate further how the E2A gene products act as growth suppressors, and will determine whether interactions with cyclin D1-dependent kinases play a critical role in this function. The spliceform products of the E2A also play a critical role in normal Bell development. Mantle cell lymphoma is associated with a chromosomal translocation that activates expression of the cyclin D1 gene. We will begin to investigate the hypothesis that enhanced expression of cyclin D1 contributes to the development of mantle cell lymphoma by blocking the functions of E2A gene products in growth control of mantle B- cells.

对于细胞周期进程或基因表达的影响 与要体现的单个细胞周期蛋白类型相关 必须发生选定底物的磷酸化。但是， 细胞周期蛋白的底物选择和磷酸化机制 依赖性激酶复合物尚不清楚。 e 蛋白质（例如E2A基因的产物）形成同型二聚体 以及与其他BHLH蛋白的异二聚体 调节组织特异性基因表达。我们已经表明 某些E蛋白异二聚体转录的激活是 细胞周期蛋白D-1依赖性激酶抑制。我们有证据表明 通过细胞周期蛋白DD1依赖性抑制肌原性BHLH调节剂 激酶是由E蛋白依赖性Kase位点介导的。研究是 提议研究抑制的机制和 确定细胞周期蛋白D1依赖性LLTase如何特别明确 识别E蛋白异二聚体和同型二聚体作为底物。 独立于其作为转录参与者的功能，表达 E2A基因产品中的certin细胞中的生长停滞 线。我们将进一步研究E2A基因产品如何作用 作为增长抑制器，并将确定是否相互作用 与细胞周期蛋白D1依赖性激酶在此起着关键作用 功能。 E2A的剪接产品也很关键 在正常的钟形发展中的作用。地幔细胞淋巴瘤是 与激活的染色体易位相关 细胞周期蛋白D1基因的表达。我们将开始调查 假设细胞周期蛋白D1的表达增强有助于 通过阻止地幔细胞淋巴瘤的发展 E2A基因产物在地幔B-的生长控制中的功能 细胞。