Elucidating the Molecular Mechanisms of Ect2 in cytokinesis and oncogenesis

阐明 Ect2 在胞质分裂和肿瘤发生中的分子机制

• 批准号: 8335585
• 负责人: Danielle Ryan Cook
• 金额: $ 3.43万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-26 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8335585
• 关键词: Accounting; Address; Anchorage-Independent Growth; Antineoplastic Agents; Cancer Etiology; Cancer cell line; Catalytic Domain; Cell Culture Techniques; Cell Line; Cell Nucleus; Cell physiology; Cessation of life; Cetuximab; Colon; Colorectal Cancer; Confusion; Cytokinesis; Cytoplasm; Development; Disease; Embryo; Epithelial Cells; Family; Fibroblasts; Fostering; Genes; Growth; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Human; In Vitro; Intestines; Large Intestine Carcinoma; Lead; Link; Lung Neoplasms; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Mutate; Mutation; Nature; Neoplasm Metastasis; Normal Cell; Oncogene Proteins; Oncogenes; Oncogenic; Patients; Phenotype; Property; Proteins; RNA Interference; Regulation; Research Personnel; Role; Signal Transduction; Techniques; Therapeutic Intervention; Tumor Cell Invasion; Tumor Cell Line; Tumor Tissue; Tumorigenicity; Validation; adenoma; anticancer research; base; bevacizumab; cancer cell; design; drug discovery; improved; in vitro Assay; in vivo; interest; knock-down; lung Carcinoma; matrigel; member; mouse model; mutant; neoplastic; neoplastic cell; overexpression; small hairpin RNA; therapeutic target; tumor growth; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): In previous years, Ras, a small GTPase oncogene has been a focus in cancer research because it is one of the most commonly mutated genes associated with all human cancers (33%). Ras is the founding member of a large superfamily of small GTPases, and recent studies have linked the abnormal activity implicated Ras superfamily proteins, in particular, the Ras homologous (Rho) GTPases to tumorigenesis. However, unlike Ras, Rho GTPases are not mutated directly in cancer, but instead their abnormal activity has been linked to their abnormal expression and/or regulation. Perhaps the most significant mechanism that has emerged in which aberrant activity of Rho GTPase is the result of abnormalities in activating proteins called RhoGEFs (guanine nucleotide exchange factors). My studies are focused on one RhoGEF, Ect2 (Epithelial cell transforming sequence 2). Ect2 is a member of the human Dbl family of RhoGEFs. Previous studies indicate that Ect2 is essential in normal mammalian cytokinesis. In contrast, abnormal overexpression of Ect2 has been observed in many cancers, and a recent study demonstrated a critical role for Ect2 in lung carcinoma cell line growth and tumorigenicity. We have found that Ect2 expression is elevated in colorectal carcinoma (CRC) patient tumor tissue, APCmin mice with spontaneous intestinal adenomas, and human CRC cell lines. There is evidence that Ect2, which is present in the nucleus of normal cells, is mislocalized into the cytoplasm in lung and brain cancers. This mislocalization may lead to inappropriate Rho activation in the cytoplasm. In addition to its RhoGEF catalytic domain, Ect2 is comprised of multiple addition domains. How Ect2 becomes aberrantly activated in cancer and whether the mechanisms of Ect2 function in normal and neoplastic cells are distinct, are poorly understood and the focus of my studies. We hypothesize that the functions of Ect2 in cytokinesis are distinct from functions which promote oncogenesis and that mislocalization may contribute to Ect2 activation in cancer. These studies will require my application of a very diverse repertoire of experimental techniques, foster my development into an independent researcher and establish my abilities to do basic and translational cancer research.

描述（申请人提供）：前几年，Ras这种小型GTP酶癌基因一直是癌症研究的焦点，因为它是与所有人类癌症相关的最常见突变基因之一（33%）。 Ras 是小 GTP 酶大超家族的创始成员，最近的研究已将 Ras 超家族蛋白（特别是 Ras 同源 (Rho) GTP 酶）的异常活性与肿瘤发生联系起来。然而，与 Ras 不同的是，Rho GTPases 在癌症中并不直接突变，而是它们的异常活性与其异常表达和/或调节有关。 Rho GTP 酶活性异常的最重要机制可能是 RhoGEF（鸟嘌呤核苷酸交换因子）激活蛋白异常的结果。我的研究重点是一种 RhoGEF，Ect2（上皮细胞转化序列 2）。 Ect2 是 RhoGEF 人类 Dbl 家族的成员。先前的研究表明，Ect2 在正常哺乳动物胞质分裂中至关重要。相比之下，在许多癌症中观察到 Ect2 的异常过度表达，最近的一项研究表明 Ect2 在肺癌细胞系生长和致瘤性中发挥着关键作用。我们发现 Ect2 在结直肠癌 (CRC) 患者肿瘤组织、患有自发性肠腺瘤的 APCmin 小鼠和人类 CRC 细胞系中表达升高。有证据表明，存在于正常细胞核中的 Ect2 在肺癌和脑癌中错误定位到细胞质中。这种错误定位可能导致细胞质中 Rho 的不适当激活。除了 RhoGEF 催化结构域外，Ect2 还包含多个附加结构域。 Ect2 如何在癌症中异常激活，以及 Ect2 在正常细胞和肿瘤细胞中的功能机制是否不同，人们对此知之甚少，也是我研究的重点。我们假设 Ect2 在胞质分裂中的功能不同于促进肿瘤发生的功能，并且错误定位可能导致癌症中 Ect2 的激活。这些研究将需要我应用非常多样化的实验技术，促进我发展成为一名独立研究人员，并建立我进行基础和转化癌症研究的能力。