PROGRESSION OF THE TRANSFORMED PHENOTYPE

转化表型的进展

• 批准号: 6171991
• 负责人: PAUL B FISHER
• 金额: $ 23.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171991
• 关键词: aging; animal genetic material tag; apoptosis; athymic mouse; cell differentiation; cell senescence; developmental genetics; enzyme activity; gene induction /repression; genetic susceptibility; genetically modified animals; human genetic material tag; human tissue; melanoma; neoplasm /cancer genetics; neoplastic process; oncogenes; oncoproteins; protein structure function; telomerase; tissue /cell culture

DESCRIPTION: Cancer is a progressive multigenic disorder characterized by defined changes in the transformed phenotype that culminates in metastatic disease. Although an area of intense investigation, the important mediators of cancer progression, remain enigmas. Determining the molecular basis of progression should lead to new opportunities for improved diagnostic and therapeutic modalities. Human melanoma cells can be induced to revert to a more normal phenotype and lose proliferative capacity irreversibly and terminally differentiate by treatment with recombinant human fibroblast interferon and mezerein. This model system is permitting a detailed molecular analysis of the genes regulated during and controlling cell growth, differentiation and the cancer phenotype. Through the use of subtraction hybridization, the investigator has identified a gene associated with induction of irreversible growth arrest, cancer reversion and terminal differentiation in human melanoma cells, melanoma differentiation associated gene-7 (mda-7). mda-7 is a novel gene that displays reduced expression in metastatic human melanoma versus normal human melanocytes. Strikingly, when metastatic human melanomas are induced to irreversibly growth arrest, terminally differentiate and lose cancerous properties, mda-7 expression increases dramatically. Immunofluorescence studies indicate that mda-7 localizes to the nucleus during cellular differentiation and growth arrest and interacts with chromatin during cellular mitosis. Ectopic expression of mda-7 results in apoptosis in diverse cancer cell types, including tumor cells with wild-type p53 or mutant for p53, Rb or p53 + Rb, but not in normal human epithelial and fibroblast cells. The mechanism by which mda-7 modifies progression and suppresses human cancer cell growth will be evaluated with a particular emphasis on its functional relationship to cellular senescence and apoptosis. These cell culture studies will make use of expression constructs and recombinant adenoviruses to xpress sense and antisense mda-7. To define the role of mda-7 in vivo, tissue and generalized gene knockouts of mda-7 will be constructed by homologous recombination. These investigations will provide important insights into a novel cancer progression gene with potential relevance to a broad spectrum of human cancers. As such, this gene may serve as a target for selectively intervening in the progression process, thereby attenuating or eliminating cancer aggressiveness and metastasis.

描述：癌症是一种进行性多基因疾病，其特征是 转化表型的明确变化最终导致转移 疾病。 尽管这是一个深入调查的领域，但重要的调解者 癌症进展的过程仍然是个谜。 确定分子基础 进展应该会带来改进诊断和治疗的新机会 治疗方式。 可以诱导人类黑色素瘤细胞恢复到 更正常的表型并不可逆地失去增殖能力 通过重组人成纤维细胞处理进行终末分化 干扰素和美泽瑞因。 该模型系统允许详细 细胞过程中调控基因的分子分析 生长、分化和癌症表型。 通过使用 通过消减杂交，研究人员鉴定出一个相关基因 诱导不可逆的生长停滞、癌症逆转和晚期 人类黑色素瘤细胞的分化，黑色素瘤分化相关 基因 7 (mda-7)。 mda-7 是一种新基因，在 转移性人类黑色素瘤与正常人类黑色素细胞。 引人注目的是，当 转移性人类黑色素瘤被诱导不可逆转的生长停滞， 终末分化并失去癌性，mda-7 表达 急剧增加。 免疫荧光研究表明 mda-7 在细胞分化和生长停滞期间定位于细胞核 并在细胞有丝分裂过程中与染色质相互作用。 异位表达 mda-7 导致多种癌细胞类型（包括肿瘤细胞）凋亡 具有野生型 p53 或 p53、Rb 或 p53 + Rb 突变体的细胞，但不包括 正常人上皮细胞和成纤维细胞。 mda-7 的作用机制 改变进展并抑制人类癌细胞的生长 评估时特别强调其功能关系 细胞衰老和凋亡。 这些细胞培养研究将利用 表达构建体和重组腺病毒以表达有义和 反义mda-7。 定义 mda-7 在体内、组织和 mda-7的通用基因敲除将通过同源构建 重组。 这些调查将为我们提供重要的见解 具有广谱潜在相关性的新型癌症进展基因 人类癌症。 因此，该基因可以作为选择性的靶标 干预进展过程，从而减弱或消除 癌症的侵袭性和转移。