E1A-CtBP interactions in oncogenic transformations

致癌转化中的 E1A-CtBP 相互作用

• 批准号: 7668342
• 负责人: GOVINDASWAMY CHINNADURAI
• 金额: $ 27.93万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7668342
• 关键词: Adenovirus E1A Proteins; Adenoviruses; Apoptosis; Binding; Biochemical; C-terminal; C-terminal binding protein; Cell Cycle; Cell Proliferation; Cell Proliferation Regulation; Centrosome; Chromatin; Conserved Sequence; Deacetylation; Development; Developmental Process; Enzymes; Excision; Exhibits; Gene Targeting; Genes; HDAC1 gene; Histone H3; Histones; Human; Knowledge; Laboratories; MYC gene; Malignant Neoplasms; Mediating; Methylation; Mutation; N-terminal; Nuclear; Nuclear Protein; Nuclear Proteins; Oncogene Proteins; Oncogenic; Pattern; Phenotype; Play; Post-Translational Protein Processing; Primates; Process; Protein Family; Proteins; Public Health; Recruitment Activity; Regulation; Role; System; Transcription Repressor/Corepressor; Transcriptional Activation; Transferase; Tumor Suppressor Proteins; Vertebrates; Viral; Work; cell transformation; cellular targeting; gene repression; genome-wide; histone modification; member; mutant; novel; promoter; protein complex; ras Oncogene; tumorigenesis; tumorigenic; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Adenovirus E1A C-terminal CR4 region interacts with the cellular CtBP family proteins, CtBP1 and CtBP2 through a highly conserved sequence motif, PLDLS. CtBP1 and CtBP2 function as transcriptional corepressors and play critical roles during development, oncogenesis and apoptosis regulation in vertebrates. They are functionally redundant for several developmental processes while exerting unique activities with regard to certain other processes. CtBP2 is highly nuclear and CtBP1 is both nuclear and cytosolic. The CtBPs mediate sequence specific transcriptional repression by recruitment of several histone modifying enzymatic constituents such as histone deacetylases, methyl transferases and a histone demethylase. Additionally, the CtBP protein complex also contains E2 and E3 enzymes that mediate SUMO modification of proteins. Adenovirus E1A mutants deficient in interaction with CtBPs exhibit a hyper-transforming phenotype in cooperation with the Ras oncogene. The transformed cells expressing E1A CR4 mutant and the Ras oncogene are highly tumorigenic and metastatic. We hypothesize that interaction of E1A with CtBP might modulate the activities of cellular proteins associated with the N-terminal region of E1A. Additionally, interaction of E1A with CtBP might also cause significant changes in the pattern of cellular CtBP target genes. In Aim 1, we will determine the effects of E1A C-terminal CR4 region and CtBPs on the Ras oncogene cooperating activity of the E1A N-terminal region. Aim 2 will elucidate the unique transcriptional activities of CtBP2 and to determine the effect of E1A on CtBP2- mediated regulation of expression of cellular target genes. Aim 3 will determine the effect of E1A in the cytosolic and nuclear functions of CtBP1. Aim 4 will elucidate the role of CtBP-associated SUMOylation machinery in transcriptional repression. Relevance to Public Health: About one third of all human cancers contain oncogenic mutations in the Ras oncogene. Similarly, the Myc oncogene also plays a dominant role in human malignancies. Certain functions shared by E1A and Myc cooperate with Ras oncogenic transformation while interaction of E1A with CtBP antagonizes such activity. Our proposed studies will harness the knowledge gained from the study of the viral oncoprotein E1A to unravel potential new mechanisms governing oncogenesis and suggest strategies to inhibit the process in humans.

描述（由申请人提供）：腺病毒E1A C末端CR4区域通过高度保守的序列基序PLDL与细胞CTBP家族蛋白CTBP1和CTBP2相互作用。 CTBP1和CTBP2在脊椎动物的发育，肿瘤发生和凋亡调节过程中起着至关重要的作用。对于几个发展过程，它们在功能上是多余的，同时就某些其他过程进行了独特的活动。 CTBP2是高度核的，CTBP1既是核和胞质的。 CTBP通过募集几种组蛋白修饰酶成分，例如组蛋白脱乙酰基酶，甲基转移酶和组蛋白脱甲基酶来介导序列特异性转录抑制。此外，CTBP蛋白复合物还含有E2和E3酶，可介导SUMO修饰蛋白质。与CTBP相互作用缺乏相互作用的腺病毒E1A突变体与RAS癌基因合作表现出超变形的表型。表达E1A CR4突变体和RAS癌基因的转化细胞是高度肿瘤和转移性的。我们假设E1A与CTBP的相互作用可能调节与E1a的N末端区域相关的细胞蛋白的活性。另外，E1A与CTBP的相互作用也可能导致细胞CTBP靶基因的模式发生显着变化。在AIM 1中，我们将确定E1A C末端CR4区和CTBP对E1A N末端区域RAS癌基合作活动的影响。 AIM 2将阐明CTBP2的独特转录活性，并确定E1A对CTBP2介导的细胞靶基因表达调节的影响。 AIM 3将确定E1A在CTBP1的胞质和核功能中的影响。 AIM 4将阐明与CTBP相关的Sumoylation机制在转录抑制中的作用。 与公共卫生有关：大约三分之一的人类癌症含有RAS癌基因中的致癌突变。同样，MYC致癌基因在人类恶性肿瘤中也起着主导作用。 E1A和MYC共享的某些功能与RAS致癌转化合作，而E1A与CTBP的相互作用拮抗了这种活性。我们提出的研究将利用从病毒果蛋白E1A的研究中获得的知识，以揭示有关造成肿瘤发生的潜在新机制，并提出抑制人类过程的策略。