Growth Inhibition by the ARF Tumor Suppressor

描述（由申请人提供）：INK4a/ARF编码ARF肿瘤抑制蛋白，是人类癌症中第二常见的失活基因。ARF通过部分定义的p53依赖性和p53非依赖性途径中的蛋白-蛋白相互作用阻止癌基因介导的转化。已经发现了许多arf相关蛋白，但除了p53拮抗剂Mdm2外，很少有蛋白在arf介导的肿瘤抑制中具有明确的作用。基于先前资助项目的工作，我们鉴定并表征了两种新的ARF相互作用蛋白，并表明它们参与ARF信号传导。Parf （Partner of ARF）是ARF p53非依赖性生长抑制活性的必需物质，而NIAM （Nuclear Interactor of ARF and Mdm2）激活p53并与ARF协同抑制细胞增殖。这两种蛋白也独立于ARF和p53维持基因组稳定性，调节DNA损伤检查点，抑制癌细胞增殖，表明它们具有与ARF和其他抗增殖途径交叉的抗癌活性。然而，Parf和NIAM调控ARF信号、基因组稳定性和细胞增殖的潜在机制尚不清楚。本研究的具体目的是确定这些新的ARF相互作用蛋白在ARF信号传导和癌变中的机制和生物学作用。目的1将确定NIAM如何增强ARF信号及其在肿瘤发生中的作用。目的2将定义Parf如何参与ARF信号传导和肿瘤抑制。分子和生化方法，以及独特的癌症小鼠模型，将被利用。

DESCRIPTION (provided by applicant): INK4a/ARF encodes the ARF tumor suppressor protein and is the second most frequently inactivated gene in human cancers. ARF prevents oncogene-mediated transformation through protein-protein interactions in partially defined p53-dependent and p53-independent pathways. Numerous ARF-associated proteins have been identified but few besides the p53 antagonist, Mdm2, have a clearly defined role in ARF-mediated tumor suppression. Based on work from the previously funded project, we identified and characterized two novel ARF interacting proteins and showed they participate in ARF signaling. Parf (Partner of ARF) is required for ARF's p53-independent growth suppressive activity, whereas NIAM (Nuclear Interactor of ARF and Mdm2) activates p53 and collaborates with ARF to inhibit cell proliferation. Both proteins also act independent of ARF and p53 to maintain genomic stability, regulate DNA damage checkpoints, and suppress cancer cell proliferation, suggesting they have anticancer activities that intersect with ARF and other antiproliferative pathways. However, the underlying mechanisms by which Parf and NIAM regulate ARF signaling, genomic stability and cell proliferation are poorly understood. The specific objective of this research is to define the mechanistic and biological roles of these novel ARF interacting proteins in ARF signaling and carcinogenesis. Aim 1 will establish how NIAM enhances ARF signaling and its role in tumorigenesis. Aim 2 will define how Parf contributes to ARF signaling and tumor suppression. Molecular and biochemical approaches, as well as unique mouse models of cancer, will be utilized. These studies will advance our fundamental understanding of how the ARF tumor suppressor and its associated proteins prevent cancer. This is highly relevant to public health because loss of ARF figures prominently in the development of nearly all types of human tumors and we cannot effectively battle cancer until we know its molecular basis. This work is expected to identify new targets for anticancer strategies and new paradigms used by tumor suppressors to prevent tumorigenesis, and as such, it should improve our ability to diagnose, treat and ultimately prevent human cancer.