Role of Km23 in Ovarian Cancer

Km23 在卵巢癌中的作用

• 批准号: 7034466
• 负责人: Kathleen M Mulder
• 金额: $ 32.53万
• 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/7034466
• 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（申请人提供）：超过80%的患者卵巢癌处于临床晚期，其5年生存率为35%。因此，非常需要开发更有前景的药物用于卵巢癌的治疗和预后。已知 TGFbeta 是一种肿瘤抑制因子，介导其生物学效应的细胞内成分也可以以这种方式发挥作用。此外，大约 75% 的卵巢癌病例，尤其是复发性疾病，会出现对 TGFbeta 生长抑制作用的抵抗。我们已经鉴定出一种新的 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 受体激活时被磷酸化。此外，km23 的表达介导特异性 TGFbeta 反应，包括上皮细胞的生长抑制。此外，我们已经在人类患者的 11 名上皮性卵巢癌中的 4 名以及 33% 的人卵巢癌细胞 (HOCC) 系中发现了 km23 的改变。由于 km23 似乎是在人类卵巢癌中发生改变的 TGFbeta 信号成分，我们假设 TGFbeta 敏感的 HOCC 中“肿瘤样”km23 改变的表达将抑制 TGFbeta 抑制这些细胞生长的能力，并产生更恶性的表型。该提案的总体目标是确定在 卵巢癌患者将导致 TGFbeta 的生长控制改变，体外表型发生更大的转变，并增加体内致瘤性。我们还将扩展对人类癌症组织的分析，以确定发生变化的频率和疾病阶段，以及正常人群中的频率。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 和运动蛋白动力蛋白中间链之间相互作用的确切域，并确定 km23 的改变如何影响这种相互作用。我们假设后两种类型的研究将有助于筛选的开发，通过筛选来识别治疗卵巢癌的新药