Cell Autonomy and Tumor Suppression by CDK inhibitors

描述（由申请人提供）：细胞周期生长抑制剂抑制肿瘤的模型通常假设关键抑制活性是肿瘤克隆固有的。最近在小鼠模型中发现肿瘤抑制基因不能完全抑制肿瘤生长，仅丢失一个基因拷贝（即单倍体肿瘤抑制不足），这提出了另一种非细胞自主的肿瘤抑制机制的可能性。例如，肿瘤克隆外部细胞中细胞周期抑制剂表达的缺失可能通过细胞外接触、旁分泌因子或血管生成介导的信号促进细胞生长。

DESCRIPTION (provided by applicant): Models of tumor suppression by cell cycle growth inhibitors commonly assume that the critical inhibitory activity is intrinsic to the tumor clone. The recent discovery of tumor suppressor genes which are incapable of fully suppressing neoplastic growth with loss of only a single gene copy (i.e. haploid insufficient tumor suppression) in mouse models raises the possibility of alternative, non cell-autonomous mechanisms of tumor suppression. For example, loss of cell cycle inhibitor expression in cells extrinsic to the neoplastic clone may enhance cell growth by signals mediated through extracellular contact, paracrine factors, or angiogenesis. This project will further our understanding of the mechanism of tumor suppression by the CDK inhibitor p27Kipl and several interacting molecules. The studies will create targeted mutations in the mouse in which p27 is either deleted or activated in specific 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 its 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 p27Kip 1 can induce adenomas and lymphomas in these tissues in a cell autonomous fashion, that is independent of the influence of factors from surrounding cells or tissues. In each model system the mechanism of tumor suppression by p27 will be further defined and the patterns of altered gene expression and cell cycle protein function will be characterized. In order to treat cancer with inhibitors of cyclin dependent kinases it is essential to identify the appropriate target cell population. Inhibition of tumorigenesis by targeting growth of normal cell populations may have the advantage of being more predictable and less prone to escape by mutations in the tumor clone.