Dissecting E2f3's role in tumorigenesis

剖析 E2f3 在肿瘤发生中的作用

• 批准号: 7146537
• 负责人: Jacqueline A. Lees
• 金额: $ 24.73万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-10 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146537
• 关键词: cell cycle; neoplasm /cancer; proteins; role

DESCRIPTION (provided by applicant): Tumor development is dependent upon the inactivation of two key tumor suppressor pathways, p16- cycD/cdk4-pRB-E2F and p19Arf-mdm2-p53, that together regulate cellular proliferation and the tumor surveillance response. This proposal focuses on one member of the E2f family, E2f3, which is a component of both the pRB and p53 networks and whose amplification has been linked to the development of human bladder and prostate tumors. E2f3 encodes two distinct proteins, called E2F3A and E2F3B that differ only in their N terminal sequences. Existing studies do not address whether the observed up-regulation of E2F3 in human tumors reflects an increase in the levels of E2F3A, E2F3B or both isoforms. Thus, it is currently unclear whether either, or both, of these proteins contribute to tumor development. The analysis of mutant mouse models has provided unequivocal proof that E2f3 acts in dose-dependent manner to promote tumor formation in vivo. This validates the mouse as model system to investigate E2f3's oncogenic activity. Preliminary studies suggest that the E2F3A and E2F3B proteins have distinct biological properties in vivo. E2F3A is believed to promote cellular proliferation by activating the transcription of genes that encode key components of the cell cycle control machinery. In contrast, E2F3B contributes to the transcriptional repression of the Art tumor suppressor and thereby impedes induction of the p53 tumor surveillance response. The goal of this proposal is to test the hypothesis that E2F3A and E2F3B have differential roles in vivo and to determine how each of these isoforms contribute to E2f3's roles in cellular proliferation, normal development and tumorigenicity. This proposal has three aims: (1) To identify the relative roles of E2F3A and E2F3B in cellular processes; (2) To use mutant mouse strains to determine the role of E2F3A and E2F3B in tumorigenesis; and (3) To investigate the mechanism of action of the E2F3 repressor by elucidating the components of the E2F3 repressor complex and identifying its specific downstream target genes.

描述（由申请人提供）：肿瘤的发展取决于两种关键肿瘤抑制途径的失活P16- CYCD/CDK4-PRB-E2F和P19ARF-MDM2-P53，它们共同调节细胞增殖和肿瘤的监测反应。该提案重点是E2F家族的一个成员E2F3，该家族是PRB和p53网络的组成部分，其扩增与人膀胱和前列腺肿瘤的发展有关。 E2F3编码两种不同的蛋白质，称为E2F3A和E2F3B，它们仅在其N末端序列上有所不同。现有的研究没有解决人类肿瘤中观察到的E2F3上调的上调是否反映了E2F3A，E2F3B或两种同工型的水平的增加。因此，目前尚不清楚这些蛋白质是否有助于肿瘤发育。突变小鼠模型的分析提供了明确的证据，表明E2F3以剂量依赖性方式作用以促进体内肿瘤形成。这验证了小鼠作为模型系统，以研究E2F3的致癌活性。初步研究表明，E2F3A和E2F3B蛋白在体内具有不同的生物学特性。据信E2F3A通过激活编码细胞周期控制机制的关键成分的基因的转录来促进细胞增殖。相反，E2F3B有助于对ART肿瘤抑制器的转录抑制，从而阻碍p53肿瘤监测反应的诱导。该提案的目的是检验以下假设：E2F3A和E2F3B在体内具有差异作用，并确定这些同工型中的每一种如何促进E2F3在细胞增殖，正常发育和肿瘤性中的作用。该提案具有三个目的：（1）确定E2F3A和E2F3B在细胞过程中的相对作用； （2）使用突变小鼠菌株来确定E2F3A和E2F3B在肿瘤发生中的作用； （3）通过阐明E2F3阻遏物复合物的成分并识别其特定的下游靶基因来研究E2F3阻遏物的作用机理。