Growth Inhibition by the ARF Tumor Suppressor

描述（由申请人提供）：INK 4a/ARF编码ARF肿瘤抑制蛋白，是人类癌症中第二个最常失活的基因。ARF通过部分确定的p53依赖性和p53非依赖性途径中的蛋白质-蛋白质相互作用阻止癌基因介导的转化。已经鉴定了许多ARF相关蛋白，但除了p53拮抗剂Mdm 2之外，很少有蛋白在ARF介导的肿瘤抑制中具有明确的作用。基于先前资助的项目的工作，我们鉴定和表征了两种新的ARF相互作用蛋白，并表明它们参与ARF信号传导。Parf（ARF的伴侣）是ARF的p53非依赖性生长抑制活性所必需的，而NIAM（ARF和Mdm 2的核相互作用物）激活p53并与ARF协作以抑制细胞增殖。这两种蛋白也独立于ARF和p53发挥作用，以维持基因组稳定性，调节DNA损伤检查点，并抑制癌细胞增殖，这表明它们具有与ARF和其他抗增殖途径交叉的抗癌活性。然而，Parf和NIAM调节ARF信号传导、基因组稳定性和细胞增殖的潜在机制知之甚少。本研究的具体目标是确定这些新的ARF相互作用蛋白在ARF信号传导和致癌中的机制和生物学作用。目的1将建立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如何有助于ARF信号传导和肿瘤抑制。将利用分子和生物化学方法以及独特的小鼠癌症模型。 这些研究将促进我们对ARF肿瘤抑制因子及其相关蛋白如何预防癌症的基本理解。这与公共卫生高度相关，因为ARF的丧失在几乎所有类型的人类肿瘤的发展中都很突出，并且在我们知道其分子基础之前，我们无法有效地对抗癌症。这项工作有望确定抗癌策略的新靶点和肿瘤抑制剂用于预防肿瘤发生的新范例，因此，它应该提高我们诊断，治疗和最终预防人类癌症的能力。

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.