PROTEOLYSIS OF LEUKEMIA--RELATED TRANSCRIPTION FACTORS

白血病蛋白水解--相关转录因子

• 批准号: 2895604
• 负责人: Gregory J Kato
• 金额: $ 11.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895604
• 关键词: cell growth regulation; complementary DNA; enzyme activity; leukemia; molecular cloning; molecular oncology; neoplastic cell; oncoproteins; proteolysis; tissue /cell culture; transcription factor; ubiquitin

DESCRIPTION: (adapted from the investigator's abstract) The most common target for chromosomal translocation in childhood leukemia is the E2A gene, which encodes the basic-helix-loop-helix transcription factors E12 and E47. These nearly ubiquitously expressed proteins have a demonstrated growth suppressive role in mammalian cells. It appears that downregulation of E2A activity is necessary for normal cell cycle progression, involving a combination of transcriptional control of the E2A gene, degradation of E2A proteins, and direct inhibition by Id proteins. Using the yeast two hybrid system, this laboratory has cloned mUBC9, a cDNA encoding a novel murine ubiquitin conjugating enzyme that may participate in the degradation of E2A proteins. This research proposal investigates the degradation of E2A protein in mammalian cells, and evaluates the role of the ubiquitin-proteasome pathway in this process, particularly the role of the mUBC9 enzyme. Data from other laboratories suggests that the yeast homolog of mUBC9 is critical to normal cell cycle progression, supporting a possible functional link between mUBC9 and growth regulatory transcription factors such as E2A proteins. The following specific aims are proposed: 1) Determine the degradation pathway of mammalian E2A proteins; 2) Evaluate the role of mUBC9 in E2A degradatio; 3) Define determinants of E2A degradation; and 4) Evaluate proposed regulatory mechanisms for E2A degradation. Accomplishment of these specific aims will provide a more general framework for understanding mechanism of regulated degradation of transcription factors as a means of controlling mammalian cell growth and differentiation. This has implications for the investigation of novel mechanisms of growth regulation with a newly demonstrated potential in oncogenesis.

描述：（改编自研究者摘要） 儿童白血病染色体易位的靶基因是E2 A基因， 其编码碱性-螺旋-环-螺旋转录因子E12和E47。 这些几乎无处不在表达的蛋白质具有经证实的生长 在哺乳动物细胞中的抑制作用。 似乎E2 A的下调 活性是正常细胞周期进程所必需的，包括 E2 A基因的转录控制、E2 A的降解 蛋白质，并通过Id蛋白直接抑制。 使用酵母双杂交 系统，本实验室克隆了mUBC 9，一个编码一种新的小鼠 可能参与E2 A降解的泛素结合酶 proteins. 本研究计划研究E2 A的降解 蛋白质在哺乳动物细胞中的作用，并评估的作用， 泛素-蛋白酶体途径在这一过程中的作用，特别是 mUBC 9酶。 其他实验室的数据表明， mUBC 9的表达对正常的细胞周期进程至关重要，支持了一种可能的 mUBC 9与生长调节转录因子之间的功能联系 例如E2 A蛋白。 建议的具体目标如下：1） 确定哺乳动物E2 A蛋白的降解途径; 2）评估E2 A蛋白的降解途径。 mUBC 9在E2 A降解中的作用：3）确定E2 A降解的决定因素; 和4）评估E2 A降解的拟议监管机制。 这些具体目标的实现将提供一个更全面的框架 为了理解转录调控降解的机制， 因子作为控制哺乳动物细胞生长和分化的手段。 这对研究新的生长机制具有重要意义 调节与肿瘤发生的新证明的潜力。