Mechanism of tumor suppression by p27

马修·费罗是一位医学肿瘤学家，研究兴趣集中在细胞周期基因的作用、癌症的发展和细胞生长的控制。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对肿瘤的抑制作用，同时使他的职业生涯从指导研究员转变为独立研究员。拟议的研究利用了Fero博士在操作小鼠胚胎中获得的技能，在实验室小鼠中产生突变，这些突变对感兴趣的基因都是特异性的，并局限于特定的组织。这些新的基因突变，然后将结合明确的小鼠模型诱导的致癌作用和基因表达分析，以确定肿瘤抑制的机制p27和它的生物化学效应在肿瘤发生。通过培育具有局限于垂体或胸腺的细胞周期基因突变的小鼠，将确定p27 kipI是否能以独立于来自周围细胞或组织的因素的影响的自主方式在这些组织中诱导腺瘤和淋巴瘤。同样，对小鼠中发生的肠道肿瘤、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进一步定义，并将表征改变的基因表达和细胞周期蛋白功能的模式。如果p27突变以细胞非自主方式引起肿瘤，则确定在p27缺陷细胞和肿瘤细胞之间起作用的信号传导途径将是重要的。然后，治疗剂可以靶向介导癌症发展的细胞周期蛋白或细胞内分子。

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.