The Physiological Function and Regulation of INK4 Genes

描述(由申请人提供)：这是CA68837的第二次竞争性更新，这项调查旨在了解CDK抑制剂INK4家族的长期目标。回顾过去10年的历程，我们高兴地看到我们作出了贡献，更值得注意的是，这一领域的其他工作人员共同取得了进步。在1993年首次发现p16INK4a之后，我们的研究重点已经从第一个资助期(1994-1999年)另外三个INK4基因的发现和生化特征，转移到第二个资助期(2000年至今)各种INK4突变小鼠品系的创造和组织学分析。在我们过去几年积累的大量表型和病理信息的基础上，这项申请中概述的研究将朝着实现以下两个长期目标迈进：(1)开发和鉴定人类肺癌和乳腺癌的小鼠模型，(2)确定INK4基因在干细胞控制中的机制和调节。结合我们在小鼠遗传和肿瘤分析、CDK活性的生化表征和G1进展的细胞研究方面的优势和成功，我们提出了实现这两个目标的三个目标。(1)探讨p18lnk4c和MEN1在肺癌抑制和干细胞调控中的作用及机制。(2)研究p18lnk4c和BRCA1在抑制乳腺肿瘤和调节乳腺干细胞增殖中的作用。(3)探讨p16基因表达的调控机制。这项研究的三个特点是：(1)广泛使用基因工程小鼠及其衍生的同基因细胞作为主要实验系统，为研究INK4家族基因的功能提供了一个高度复杂的生理环境。(2)在一项研究中联合研究两个具有肿瘤抑制功能的INK4基因，不仅可以全面了解它们各自的功能，还可以揭示可能的功能补偿，并可以比较它们的调节机制。(3)该基因家族在肿瘤抑制、干细胞控制和不同类型人类癌症小鼠模型的建立中的关键作用。

DESCRIPTION (provided by applicant): This is the second competing renewal of CA68837, an investigation aimed at the long-term goal of understanding the INK4 family of CDK inhibitors. Looking back at the journey over the past 10 years, we are pleased to see the contributions we made and, more remarkably, the advancement achieved collectively by others working in this field. The focus of our own research, following the initial discovery of p16Ink4a in 1993, has moved forward from the discovery and biochemical characterization of three additional INK4 genes during the first funding period (1994 - 1999), to the creation and histological analyses of various Ink4 mutant mouse strains during the second funding period (2000 - present). Built upon the large volume of phenotypical and pathological information we accumulated over the past several years, the research outlined in this application will move toward achieving the following two long-term goals: (1) developing and characterizing mouse models for human lung and breast cancers, and (2) to determine the mechanism and regulation of INK4 genes in stem cell control. Combining our strength and success in genetic and tumor analysis in mice, biochemical characterization of CDK activities, and cellular studies of G1 progression, we propose three aims to achieve these two goals. (1) To determine the function and mechanism of p18lnk4c and Men1 in lung tumor suppression and stem cell control. (2) To determine how p18lnk4c and Brca1 functionally collaborate to suppress mammary tumors and regulate mammary stem cell expansion. (3) To determine the mechanisms regulating p16 gene expression. Three features of this investigation are: (1) Extensive use of genetically engineered mice and their derived isogenic cells as the primary experimental system, providing a highly sophisticated physiological setting to examine the function of INK4 family genes. (2) A combination of investigation of two INK4 genes with demonstrated tumor suppression function in one study would not only provide a comprehensive view of their individual function, but also uncover possible functional compensation and allow a comparison of their regulatory mechanisms. (3) The critical importance of this gene family in tumor suppression, stem cell control, and development of mouse models for different type of human cancers.