The Molecular Mechanism for E2A Tumor Suppressor

E2A肿瘤抑制因子的分子机制

• 批准号: 7668730
• 负责人: YIN CHUN LIN
• 金额: $ 5.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7668730
• 关键词: Acute T Cell Leukemia; Adult; Affinity; Alternative Splicing; BHLH Protein; Binding; Binding Sites; Bone Marrow Cells; C-KIT Gene; CD44 gene; Cell Cycle Progression; Cell Line; Cell Lineage; Cell Maturation; Cell Proliferation; Cells; Commit; Complex; Consensus Sequence; DNA Binding; DNA Sequence Rearrangement; Data; Development; Dominant-Negative Mutation; Drug Design; E protein; E-Box Elements; Family member; Gene Rearrangement; Generations; Genes; Genetic Transcription; Growth; Helix-Turn-Helix Motifs; Hematopoietic; Histone Deacetylase; Human; IL2RA gene; Link; Lymphocyte; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Myeloid Cells; Names; Normal Cell; Oncogene Proteins; Patients; Peptides; Population; Preclinical Drug Evaluation; Process; Protein Isoforms; Proteins; Recruitment Activity; Regulation; Regulatory Element; Research Design; Role; Signal Transduction; Staging; T-Cell Development; T-Lymphocyte; TCF3 gene; Thymocyte Development; Thymus Gland; Transgenic Mice; Tumor Suppressor Proteins; V(D)J Recombination; Yin; base; c-myc Genes; cancer therapy; cancer type; cell growth; fetal; gene repression; helix-loop-helix protein differentiation inhibitor; histone acetyltransferase; inhibitor/antagonist; member; mouse model; neoplastic cell; notch protein; overexpression; peripheral blood; progenitor; promoter; receptor; selective expression; thymocyte; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The oncoprotein Myc is an important regulator for cell growth and cellular proliferation. When Myc is overexpressed and unregulated, it contributes to the developments of many types of cancers. In a transgenic mouse model, myc overexpression has been shown to result in tumorigenesis. Conversely, the inactivation of Myc in tumor cells causes tumor regression. Previous studies and preliminary data shown here suggest that E2A likely functions as a tumor suppressor, in part, by regulating cell growth and cellular proliferation. I propose to continue to elucidate the molecular mechanism of E2A. In particular, how E2A and Myc are linked to regulate cell growth and cellular proliferation in normal cells as well as tumor cells. In addition, I propose to determine whether E2A can interfere with the cell growth of T-ALL (acute T-cell lymphoblastic leukemia). Specific Aims: (1) to examine how E47 controls cell growth in developing thymocytes (2) to identify potential regulatory elements in the Myc and Mad locus responsive to E47 (3) and to determine whether enforced expression of E47 interferes with the cell growth of T-ALL. Study design: To determine how E47 controls cell growth in developing thymocytes, I will utilize a strategy in which E47 and Myc activity can be manipulated during the beta selection stage or the cell growth stage of thymocyte development. By examining the effects on growth when these activities are interfered, I should be able to determine how E47 and Myc are linked to regulate cell growth in normal cells. To identify potential E47 binding sites at the myc and mad promoters, I will first determine whether E47 binds directly to the promoters to regulate the transcriptions of myc and mads. If E47 binds to the promoters, I will identify the E47 regulatory elements. Once I elucidate the molecular mechanism for E2A tumor suppressor, I will determine whether enforced expression of E47 can interfere with the cell growth of T-ALL cells. I will use a well established murine model for T-ALL and a known human patient T-ALL cell line. Relevance: As mentioned earlier, Myc overexpression is commonly associated with cancer. Therefore, ways to downregulate Myc activity could be potential treatments for cancer. By establishing a molecular mechanism for E2A, we can design drugs that activate E2A activity. With the available human T-ALL mouse model, it will provide a powerful way to screen for drugs that can potentially treat T-ALL as well as other types of cancers.

描述（由申请人提供）：癌蛋白Myc是细胞生长和细胞增殖的重要调节剂。当 Myc 过度表达且不受调节时，它会促进多种癌症的发展。在转基因小鼠模型中，myc 过度表达已被证明会导致肿瘤发生。相反，肿瘤细胞中Myc的失活会导致肿瘤消退。先前的研究和此处显示的初步数据表明，E2A 可能部分通过调节细胞生长和细胞增殖发挥肿瘤抑制因子的作用。我建议继续阐明E2A的分子机制。特别是，E2A 和 Myc 如何相互关联来调节正常细胞和肿瘤细胞的细胞生长和增殖。此外，我建议确定E2A是否可以干扰T-ALL（急性T细胞淋巴细胞白血病）的细胞生长。具体目标： (1) 检查 E47 如何控制发育中胸腺细胞的细胞生长 (2) 识别 Myc 和 Mad 基因座中对 E47 敏感的潜在调控元件 (3) 并确定 E47 的强制表达是否会干扰胸腺细胞的生长高的。研究设计：为了确定 E47 如何控制胸腺细胞发育中的细胞生长，我将采用一种策略，在胸腺细胞发育的 β 选择阶段或细胞生长阶段可以操纵 E47 和 Myc 活性。通过检查这些活动受到干扰时对生长的影响，我应该能够确定 E47 和 Myc 如何与调节正常细胞的细胞生长相关。为了确定 myc 和 mad 启动子上潜在的 E47 结合位点，我将首先确定 E47 是否直接与启动子结合以调节 myc 和 mads 的转录。如果 E47 与启动子结合，我将识别 E47 调控元件。一旦我阐明了 E2A 肿瘤抑制因子的分子机制，我将确定 E47 的强制表达是否会干扰 T-ALL 细胞的细胞生长。我将使用一个完善的 T-ALL 小鼠模型和一个已知的人类患者 T-ALL 细胞系。相关性：如前所述，Myc 过度表达通常与癌症相关。因此，下调 Myc 活性的方法可能是治疗癌症的潜在方法。通过建立E2A的分子机制，我们可以设计激活E2A活性的药物。借助现有的人类 T-ALL 小鼠模型，它将提供一种强大的方法来筛选可能治疗 T-ALL 以及其他类型癌症的药物。