PATHOGENESIS OF CANCER--ROLE OF EGF RECEPTOR ENDOCYTOSIS

描述：(改编自研究者的摘要)生长因子受体 在细胞增殖、分化和调控死亡中发挥核心作用。 对来自这些受体的特定信号的不良调节是一个重要的 肿瘤发生和发展的机制。表皮生长因子 受体(EGFR)和ErbB酪氨酸激酶家族的其他成员是重要的 在人类肿瘤中，特别是在乳腺、宫颈、卵巢、胃、膀胱 和肺癌，以及神经母细胞瘤/胶质母细胞瘤。这些受体有 成为癌症预防和治疗的主要靶点。已经使用了EGFR 作为几种癌症的预后标志物，EGFRs的抗体已经 作为一种抗癌疗法被测试。然而，抗体的一般局限性 治疗和正常组织中EGFR的存在需要新的 特异性抑制肿瘤细胞中的EGFR并将其用作 癌症不同阶段的标志物。 由配体激活的EGFR通常会导致快速的内吞作用和 下调对EGFR的监管。通过下调EGFR，内吞作用起到 EGFR信号持续时间和强度的主要调节者。这个 这个过程的限速步骤是受体内化，通过 笼罩着网状蛋白的坑。相比之下，金融机构的内部化和下调 在许多过度表达EGFR的癌细胞中，EGFR可以忽略不计。我们 假设EGFR通过包被凹坑的内吞途径是饱和的 因为它的能力受到特定蛋白质含量低的限制 负责将激活的EGFR招募到涂层坑中。的目标是 该提议是为了确定这些被覆盖的坑“招募者”(CPR)，并 描述它们如何参与癌细胞中EGFR的下调。 CPR的功能特征将使用新的 我们开发的活细胞中的蛋白质-蛋白质相互作用分析。一个 更长期的目标是确定CPRs在肿瘤中的表达和调节 其中EGFR在转型中非常重要。我们的预测是CPR是 在正常细胞和肿瘤细胞中差异表达。例如，低水平的 CPRs在癌组织中的表达可能是其维持的主要原因 在这些细胞中有大量激活的EGFR。因此，CPR很可能是 癌症防治的重要新靶点。CPR分子将会是 在良性宫颈粘膜、鳞状上皮内病变和 以确定CPR分析是否在 潜在性红斑狼疮患者预后判断及指导治疗 宫颈粘膜癌前病变或恶性病变。

DESCRIPTION: (Adapted from the investigator's abstract) Growth factor receptors play a central role in cell proliferation, differentiation and regulated death. Poor regulation of specific signals from these receptors is an important mechanism of cancer pathogenesis and progression. The epidermal growth factor receptor (EGFR) and other members of ErbB tyrosine kinase family are important in human neoplasia, particularly in breast, cervical, ovary, stomach, bladder and lung carcinomas, and in neuroblastomas/glioblastomas. These receptors have become major targets for cancer prevention and therapy. The EGFR has been used as a prognostic marker in several types of cancer, and an antibody to EGFRs has been tested as an anti-cancer therapy. However, general limitations of antibody therapy and the presence of EGFRs in normal tissue pose a need for new approaches to specifically inhibit EGFRs in tumor cells and to use the EGFR as a marker of the various stages of cancer. Activation of EGFRs by ligand normally results in the rapid endocytosis and down-regulation of EGFRs. By down-regulating EGFRs, endocytosis serves as the major regulator of the duration and intensity of signaling by the EGFR. The rate-limiting step of this process is receptor internalization via clathrin-coated pits. In contrast, the internalization and down-regulation of EGFRs is negligible in many types of cancer cells that overexpress EGFRs. We hypothesize that the endocytic pathway of EGFRs via coated pits is saturable because its capacity is limited by the low amount of specific proteins responsible for recruitment of activated EGFRs into coated pits. The goal of the proposal is to identify these coated pit "recruiters" (CPRs) and to characterize how they participate in down-regulation of EGFR in cancer cells. The functional characterization of CPRs will be accomplished using novel protein-protein interaction assays in living cells that we have developed. A longer-term goal is to define the expression and regulation of CPRs in tumors where EGFR is important in the transformation. Our prediction is that CPRs are differentially expressed in normal and tumor cells. For instance, low levels of expression of CPRs in cancer tissue may be a primary reason of the maintenance of large amounts of activated EGFR in these cells. Therefore, CPRs may well be important new targets for cancer prevention and therapy. CPR molecules will be evaluated in benign cervical mucosa, squamous intraepithelial lesions, and squamous cell carcinomas to determine if CPR analysis could play a role in the determination of prognosis and in guiding therapy of patients with potentially premalignant or malignant lesions of the cervical mucosa.