Role of Km23 in Ovarian Cancer

Km23 在卵巢癌中的作用

• 批准号: 6889653
• 负责人: Kathleen M Mulder
• 金额: $ 33.31万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6889653
• 关键词: athymic mouse; biological signal transduction; cell line; chimeric proteins; clinical research; dynein ATPase; fluorescence resonance energy transfer; growth factor receptors; human tissue; intermediate filaments; laser capture microdissection; matrix assisted laser desorption ionization; mutant; neoplasm /cancer classification /staging; neoplasm /cancer genetics; nucleic acid purification; ovary neoplasms; phenotype; phosphorylation; protein kinase C; protein protein interaction; protein structure function; receptor expression; site directed mutagenesis; transforming growth factors; tumor suppressor proteins

DESCRIPTION (provided by applicant): Ovarian cancer presents at a late clinical stage in more than 80% of patients It is associated with a 5-year survival rate of 35% Thus, there is a great need to develop more promising agents for the treatment and prognosis of ovarian cancer. TGFbeta is known to be a tumor suppressor, and intracellular components that mediate its biological effects can also function in this manner. Further, resistance to the growth inhibitory effects of TGFbeta occurs in approximately 75% of ovarian cancer cases, especially with recurrent disease. We have identified a novel TGFbeta signaling component, termed km23, which is also a light chain of the motor protein dynein. This cytoplasmic component interacts with the TGFbeta receptors and is phosphorylated upon TGFbeta receptor activation. Further, expression of km23 mediates specific TGFbeta responses, including growth inhibition of epithelial cells Moreover, we have identified alterations in km23 in 4 out of 11 epithelial ovarian cancers from human patients, and in 33% of human ovarian cancer cell (HOCC) lines. Since km23 appears to be a TGFbeta signaling component that is altered in human ovarian cancer, we hypothesize that expression of the "tumor-like" km23 alterations in TGFbeta-sensitive HOCCs will suppress the ability of TGFbeta to inhibit the growth of these cells, and produce a more malignant phenotype The overall goal of this proposal is to determine whether the km23 alterations identified in ovarian cancer patients will result in altered growth control by TGFbeta, a more transformed phenotype in vitro, and increased tumorigenicities in vivo. We will also extend our analyses of human cancer tissues to determine the frequency and stage of disease at which the changes occur, as well as the frequency in the normal population. Additional studies will identify the kinase that phosphorylates km23, as well as the precise km23 phosphorylation sites. Finally, we will identify the exact domains of interaction between km23 and the intermediate chain of the motor protein dynein, and determine how alterations in km23 affect this interaction. We hypothesize that the latter two types of studies will assist in the development of screens by which to identify novel agents for the treatment of ovarian cancer

描述（由申请人提供）：在超过80％的患者中，卵巢癌在晚期临床阶段表现出来，其5年生存率为35％，因此，非常需要开发更多有希望的药物来治疗和预后的卵巢癌。已知TGFBETA是肿瘤抑制剂，介导其生物学作用的细胞内成分也可以以这种方式起作用。此外，在大约75％的卵巢癌病例中，尤其是复发性疾病，对TGFBETA的生长抑制作用的抗性发生。我们已经确定了一种新型的TGFBETA信号传导成分，称为KM23，它也是运动蛋白动力蛋白的轻链。该细胞质成分与TGFBETA受体相互作用，并在TGFBETA受体激活后磷酸化。此外，KM23的表达介导了特定的TGFBETA反应，包括对上皮细胞的生长抑制作用，我们已经确定了来自人类患者的11种上皮卵巢癌的KM23的变化，以及33％的人类卵巢癌细胞（HOCC）系列的变化。由于KM23似乎是人类卵巢癌中改变的TGFBETA信号传导成分，因此我们假设表达TGFBETA敏感的HOCC中“肿瘤样” KM23的变化的表达将抑制TGFBETA的能力，以抑制TGFBET的能力，以抑制这些细胞的生长，以确定这些细胞的生长，并抑制了这些型号的整体型号，是否抑制了这些型号的整体现象，是否抑制了整个型号的现象。卵巢癌患者将导致TGFBETA的生长控制改变，TGFBETA在体外发生了更转化的表型，并增加了体内肿瘤性。我们还将扩展对人类癌组织的分析，以确定发生变化发生的疾病的频率和阶段以及正常人群的频率。其他研究将确定磷酸化KM23的激酶以及精确的KM23磷酸化位点。最后，我们将确定KM23与运动蛋白动力蛋白的中间链之间相互作用的确切结构域，并确定KM23中的变化如何影响这种相互作用。我们假设后两种研究将有助于开发筛查，以鉴定新的药物治疗卵巢癌