Tumor gene expression in vitro and in vivo

我国的生长调节研究主要涉及癌基因和抑癌基因 基因作为正常和肿瘤生长的正和负调节因子。主电流 项目涉及一个肿瘤抑制基因家族，DLC 1 -3，以及它的靶点， 规范。DLC 1在多种肿瘤中是失活的，但其机制的许多方面都是不稳定的。 人们对行动仍然知之甚少。它通过其Rho-GAP活性负调节Rho，但它 可能编码其他活性，因为已知其他Rho-GAP在 癌我们先前已经确定DLC 1与张力蛋白基因的成员相互作用， 家族，通过DLC 1的一个区域，以前没有鉴定出其功能， 显示这种相互作用有助于DLC 1的生长抑制活性。协同 研究中，我们发现DLC 1的Rho-GAP结构域与p120-Ras-GAP相互作用， 干扰DLC 1的Rho-GAP活性。我们目前正在寻找其他 DLC 1的活性，以更好地了解其作用机制，并更充分地证实 我们假设DLC 1在癌症中经常失活，因为它编码一种 多功能蛋白质考虑到DLC 1和DLC 2之间相互作用的生物学重要性， tensin基因家族（tensin 1 -4）在肿瘤中的作用。Tensin-3是 发现对来自非小细胞肺的细胞系的致瘤性做出有力贡献 癌症（NSCLC）、乳腺癌和黑色素瘤，以及来自转基因小鼠乳腺癌 模型张力蛋白-3SH2结构域具有以前未描述的酪氨酸特征 被Src磷酸化，这种磷酸化有助于一些 促癌配体，如FAK和p130 Cas，结合SH 2结构域。基因突变 SH 2结构域中的酪氨酸降低了它们的结合和张力蛋白-3的生物活性。我们 还鉴定了Rho GT3家族蛋白Cdc 42活性的负调节 RhoA作为E-cadherin负调控肿瘤生长的新机制， 的NSCLC细胞系。在所研究的每个品系中，主要活性Rho GT3家族成员Cdc 42 或RhoA有助于细胞系的致癌特性，并受到 E-钙粘蛋白。

Our growth regulation research has been concerned with oncogenes and tumor suppressor genes as positive and negative regulators of normal and neoplastic growth. The main current project is concerned with a tumor suppressor gene family, DLC1-3, and the targets that it regulates. DLC1 is inactivated in a variety of tumors, but many aspects of it mechanism of action remain poorly understood. It negatively regulates Rho, via its Rho-GAP activity, but it is likely to encode other activities, as other Rho-GAPs are not known to be inactivated in cancer. We have previously determined that DLC1 interacts with members of the tensin gene family, via a region of DLC1 for which no function had been previously identified, and have shown this interaction contributes to the growth suppressor activity of DLC1. In collaborative studies, we have found that the Rho-GAP domain of DLC1 interacts with p120-Ras-GAP and interferes with the Rho-GAP activity of DLC1. We are currently trying to identify other activities of DLC1 to understand its mechanism of action better and to more fully substantiate our hypothesis that DLC1 is frequently inactivated in cancer because it encodes a multifunctional protein. Given the biological importance of the interaction between DLC1 and tensin, we have explored the role of this gene family (tensin1-4) in tumors. Tensin-3 was found to make a potent contribution to the oncogenicity of cell lines from non-small cell lung cancer (NSCLC), breast cancer, and melanoma, as well as from a transgenic mouse breast cancer model. The tensin-3 SH2 domain has the previously undescribed characteristic of its tyrosines being phosphorylated, by Src, and this phosphorylation contributes to the ability of some pro-oncogenic ligands, such as FAK and p130Cas, to bind the SH2 domain. Mutation of the the tyrosines in the SH2 domain reduces their binding and the biological activity of tensin-3. We have also identified negative regulation of the activity of Rho GTPase family proteins, Cdc42 and RhoA, as a new mechanism by which E-cadherin can negatively regulate the neoplastic growth of NSCLC lines. In each line studied, the predominantly active Rho GTPase family member Cdc42 or RhoA contributed to the oncogenic properties of the line and was potently regulated by E-cadherin.