Growth Inhibition by the ARF Tumor Suppressor

描述(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通过部分确定的P53依赖和P53非依赖途径中的蛋白质-蛋白质相互作用来阻止癌基因介导的转化。已鉴定出许多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。基于之前资助的项目，我们鉴定并鉴定了两个新的ARF相互作用蛋白，并表明它们参与了ARF信号转导。ARF的p53非依赖性生长抑制活性需要PARF(ARF的伙伴)，而NIAM(ARF和MDM2的核相互作用因子)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发挥作用，以维持基因组稳定，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、基因组稳定性和细胞增殖的潜在机制尚不清楚。这项研究的具体目的是确定这些新的ARF相互作用蛋白在ARF信号转导和癌症发生中的机制和生物学作用。目标1将确定NIAM如何增强ARF信号及其在肿瘤发生中的作用。目标2将定义PARF如何在ARF信号和肿瘤抑制中发挥作用。将利用分子和生化方法，以及独特的癌症小鼠模型。 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。这与公众健康高度相关，因为ARF的丧失在几乎所有类型的人类肿瘤的发展中都占有重要地位，在我们了解其分子基础之前，我们无法有效地与癌症作斗争。这项工作有望确定抗癌策略的新靶点和肿瘤抑制因子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.