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区通过高度保守的序列基序PLDLS与细胞CtBP家族蛋白CtBP1和CtBP2相互作用。 CtBP1 和 CtBP2 作为转录辅阻遏物发挥作用，在脊椎动物的发育、肿瘤发生和细胞凋亡调节过程中发挥关键作用。它们对于某些发育过程来说在功能上是多余的，同时对于某些其他过程发挥独特的活动。 CtBP2 是高度核的，而 CtBP1 既是核的又是胞质的。 CtBP 通过招募几种组蛋白修饰酶成分（例如组蛋白脱乙酰酶、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 蛋白质复合物还含有介导蛋白质 SUMO 修饰的 E2 和 E3 酶。与 CtBP 相互作用缺陷的腺病毒 E1A 突变体表现出与 Ras 癌基因合作的超转化表型。表达E1A CR4突变体和Ras癌基因的转化细胞具有高度致瘤性和转移性。我们假设 E1A 与 CtBP 的相互作用可能调节与 E1A N 末端区域相关的细胞蛋白的活性。此外，E1A 与 CtBP 的相互作用也可能导致细胞 CtBP 靶基因模式的显着变化。在目标 1 中，我们将确定 E1A C 末端 CR4 区域和 CtBP 对 E1A N 末端区域 Ras 癌基因协同活性的影响。目标 2 将阐明 CtBP2 独特的转录活性，并确定 E1A 对 CtBP2 介导的细胞靶基因表达调节的影响。目标 3 将确定 E1A 对 CtBP1 胞质和核功能的影响。目标 4 将阐明 CtBP 相关 SUMO 化机制在转录抑制中的作用。 与公共健康的相关性：大约三分之一的人类癌症含有 Ras 致癌基因的致癌突变。同样，Myc 癌基因在人类恶性肿瘤中也发挥着主导作用。 E1A 和 Myc 共有的某些功能与 Ras 致癌转化协同作用，而 E1A 与 CtBP 的相互作用则拮抗此类活性。我们提出的研究将利用从病毒癌蛋白 E1A 研究中获得的知识来揭示控制肿瘤发生的潜在新机制，并提出抑制人类这一过程的策略。