Mechanism of tumor suppression by p27

p27抑制肿瘤的机制

• 批准号: 6522904
• 负责人: Matthew L Fero
• 金额: $ 15.53万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522904
• 关键词: T lymphocyte; adenoma; benign prostate hyperplasia; cell cycle proteins; chemical carcinogenesis; enzyme inhibitors; gastrointestinal neoplasms; gene mutation; gene targeting; genetically modified animals; laboratory mouse; lymphoma; male; mixed tissue /cell culture; murine leukemia virus; neoplasm /cancer; neoplasm /cancer genetics; nitrosourea; pituitary neoplasms; proopiomelanocortin; protein kinase; thymus neoplasms; tumor suppressor proteins

Matthew Fero is a medical oncologist with research interests which focus on the role of cell cycle genes the development of cancer and in the control of cell growth. This award permits Dr. Fero to further our understanding of tumor suppression by the cell cycle inhibitor (CKI) gene p27kip1, while making a transition in his career from the position of a mentored researcher to an independent investigator. The proposed studies utilize the skills Dr. Fero has acquired in the manipulation of the mouse embryo to produce mutations in laboratory mice which are specific both to genes of interest and confined to particular tissues. These novel gene mutations will then be combined with well defined murine models of induced carcinogenesis and gene expression analysis to define the mechanism of tumor suppression of p27 and it's biochemical effects in tumorigenesis. By developing mice which harbor cell cycle gene mutations confined to the pituitary or thymus it will be determined whether the p27kipI can induce adenomas and lymphomas in these tissues in an autonomous fashion, that is independent of the influence of factors from surrounding cells or tissues. Likewise analysis of intestinal tumors, lymphomas and prostate tumors developing in mice which are genetic mosaics for p27 gene mutations will determine whether these tumors also arise in an autonomous fashion. The mechanism of tumor suppression by p27 will be further defined in each model system and the patterns of altered gene expression and cell cycle protein function will be characterized. If p27 mutations cause tumors in a cell non-autonomous fashion it will be important to determine the signaling pathway which acts between the p27 deficient cell and the neoplastic cell. Therapeutic agents may then be targeted at either the cell cycle proteins or the intracellular molecules which mediate cancer development.

Matthew Fero 是一位医学肿瘤学家，其研究兴趣集中在细胞周期基因在癌症发展和细胞生长控制中的作用。该奖项使 Fero 博士能够进一步了解细胞周期抑制剂 (CKI) 基因 p27kip1 抑制肿瘤的作用，同时将他的职业生涯从指导研究员转变为独立研究者。拟议的研究利用费罗博士在操纵小鼠胚胎方面获得的技能，在实验室小鼠中产生突变，这些突变既针对感兴趣的基因，又局限于特定的组织。然后，这些新的基因突变将与明确的诱导癌变小鼠模型和基因表达分析相结合，以确定 p27 的肿瘤抑制机制及其在肿瘤发生中的生化作用。通过培养仅限于垂体或胸腺的细胞周期基因突变的小鼠，将确定 p27kipI 是否能够以自主方式在这些组织中诱导腺瘤和淋巴瘤，即独立于周围细胞或组织因素的影响。同样，对小鼠体内发生的肠道肿瘤、淋巴瘤和前列腺肿瘤（它们是 p27 基因突变的遗传嵌合体）的分析将确定这些肿瘤是否也以自主方式出现。 p27 抑制肿瘤的机制将在每个模型系统中得到进一步定义，并且基因表达和细胞周期蛋白功能改变的模式将得到表征。如果 p27 突变以细胞非自主方式引起肿瘤，那么确定 p27 缺陷细胞和肿瘤细胞之间作用的信号传导途径将很重要。然后治疗剂可以靶向细胞周期蛋白或介导癌症发展的细胞内分子。