Determination of molecular pathways regulating LOT1 mediated growth suppressions

确定调节 LOT1 介导的生长抑制的分子途径

• 批准号: 6667421
• 负责人: THOMAS C. HAMILTON
• 金额: $ 16.54万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-27 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6667421
• 关键词: biological signal transduction; cell line; gene expression; genetic regulation; human tissue; ovary neoplasms; tissue /cell culture; tumor suppressor genes

DESCRIPTION: (Applicant's Description) We previously reported discovery of the LOT1 (Lost On Transformation) gene (GenBank accession #U72620) through analysis of gene expression differences between normal and malignantly transformed rat ovarian surface epithelial (ROSE) cells, an in vitro ovarian cancer model. The gene frequently shows decreased or lost expression in independently transformed ROSE cell lines compared to the normal progenitor cells. Based on these observations, we considered the LOT1 gene a potential candidate gene involved in regulating human ovarian cancer. In an effort to translate this finding in a model system to human disease, we cloned the human homologue, LOT1 (GenBank accession #72621). Interestingly, the human gene maps to chromosome 6 at band 25 (6q25), which is a site for loss of heterozygosity (LOH) in ovarian cancer and many other solid tumors. Expression of the LOT1 gene was lost or decreased in seven out of eleven ovarian cancer cell lines consistent with the findings in the rat ovarian cancer cell lines. The deduced amino acid sequence of LOT1 indicates that it is a zinc-finger motif containing protein with domains characteristic of transcription factors. Functional assays proved that it is a nuclear protein with a potential role as a transcription factor. We also found that the LOT1 gene is involved in the epidermal growth factor receptor (EGFR) signaling pathway and is a negative regulator of the ovarian cancer cell growth. The goal of this proposal is to further ascertain the clinical importance of LOT1 by determining how down-regulation or lost expression/function of LOT1 transduces anti-proliferative signals and behaves as a tumor/growth suppresser gene regulating other genes, which inhibit the malignant phenotype. To elaborate these mechanisms we will investigate the upstream regulators and downstream events associated with the action of the LOT protein and to determine how these normal processes are perturbed in ovarian malignancies. Hopefully, these endeavors will result in a better understanding of the ovarian cancer development and/or progression and provide a basis for more effective diagnosis, treatment, and/or management of the disease.

描述：（申请人的描述）我们之前报道了通过分析正常和恶性转化的大鼠卵巢表面上皮（ROSE）细胞（一种体外卵巢癌）之间的基因表达差异，发现了LOT1（转化丢失）基因（GenBank登录号#U72620）模型。 与正常祖细胞相比，该基因在独立转化的 ROSE 细胞系中经常表现出表达减少或丢失。基于这些观察，我们认为 LOT1 基因是参与调节人类卵巢癌的潜在候选基因。 为了将模型系统中的这一发现转化为人类疾病，我们克隆了人类同源物 LOT1（GenBank 登录号 #72621）。有趣的是，人类基因映射到 6 号染色体带 25 (6q25)，这是卵巢癌和许多其他实体瘤中杂合性丢失 (LOH) 的位点。 LOT1 基因的表达在 11 种卵巢癌细胞系中的 7 种中丢失或降低，与大鼠卵巢癌细胞系中的发现一致。 LOT1 的推导氨基酸序列表明它是一个含有锌指基序的蛋白质，具有转录因子特征结构域。 功能分析证明它是一种核蛋白，具有作为转录因子的潜在作用。 我们还发现LOT1基因参与表皮生长因子受体（EGFR）信号通路，并且是卵巢癌细胞生长的负调节因子。 该提案的目的是通过确定 LOT1 的表达/功能下调或丧失如何转导抗增殖信号并作为肿瘤/生长抑制基因调节其他基因（抑制恶性表型），进一步确定 LOT1 的临床重要性。 。 为了详细阐述这些机制，我们将研究与 LOT 蛋白作用相关的上游调节因子和下游事件，并确定这些正常过程在卵巢恶性肿瘤中如何受到干扰。 希望这些努力能够更好地了解卵巢癌的发生和/或进展，并为更有效地诊断、治疗和/或管理该疾病提供基础。