The Physiological Function and Regulation of INK4 Genes

描述（由申请人提供）：这是CA 68837的第二次竞争性更新，这是一项旨在了解INK 4家族CDK抑制剂的长期目标的研究。回顾过去10年的历程，我们高兴地看到我们作出的贡献，更值得注意的是，在这一领域工作的其他人集体取得了进展。在1993年首次发现p16 Ink 4a之后，我们自己的研究重点已经从第一个资助期（1994 - 1999）期间发现和生化表征另外三个INK 4基因，到第二个资助期（2000年至今）期间各种Ink 4突变小鼠品系的创建和组织学分析。基于我们在过去几年中积累的大量表型和病理信息，本申请中概述的研究将朝着实现以下两个长期目标发展：（1）开发和表征人类肺癌和乳腺癌的小鼠模型，以及（2）确定干细胞控制中INK 4基因的机制和调控。结合我们在小鼠遗传和肿瘤分析、CDK活性的生化表征以及G1进展的细胞研究方面的优势和成功，我们提出了三个目标来实现这两个目标。(1)探讨p18 lnk 4c和Men 1在肺肿瘤抑制和干细胞调控中的作用及机制。(2)确定p18 lnk 4c和Brca 1如何在功能上协同抑制乳腺肿瘤和调节乳腺干细胞扩增。(3)探讨p16基因表达的调控机制。本研究的三个特点是：（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的实验系统，为研究INK 4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，对两个具有肿瘤抑制功能的INK 4基因进行联合研究，不仅可以全面了解其各自的功能，还可以发现可能的功能补偿，并比较其调控机制。(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的小鼠模型的开发中至关重要。

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.