Regulation and Role of Ornithine Decarboxylase in Cell Proliferation and Cancer

项目摘要 Myc家族的致癌转录因子在70%的人类癌症中被激活，它们调节 转录基因组的大片段(10-15%)以协调新陈代谢、细胞生长和分裂， 差异化、发展性。此外，Myc位于激活的Ras癌蛋白的下游，Ras癌蛋白是 在人类癌症中频繁突变，其中RAS信号损害Myc蛋白的周转并增加 它的转录活性。在过去的资金周期中，我们证明了Myc的增殖性反应 对肿瘤的发展是有限制的。值得注意的是，这条路径严格依赖于单个Myc 转录靶标，鸟氨酸脱羧酶(ODC)，多胺生物合成的限速酶。 在这里，我们展示了使用ODC自杀抑制剂DFMO的治疗，或简单地将 ODC(在ODC+/-小鼠中)，使易患肿瘤的Myc转基因小鼠的寿命延长三倍，而且它还会损害 表皮癌变，与激活RAS突变有关。总而言之，这些发现 表明以ODC为靶点将在癌症预防中具有广泛的好处，这一事实现已在 正在进行的人类癌症化学预防试验。此外，我们确定以ODC为目标会禁用Myc 选择性地影响Myc引起细胞周期蛋白降解的增殖反应 依赖的激酶抑制物p27Kip1，一种肿瘤抑制物，通过S期抑制进入和进展。 在这里，我们首先证明了Myc通过激活Cks1，a的转录来触发p27Kip1的降解 SCFSkp2 E3泛素连接酶复合体的组成部分，指导p27Kip1的破坏。令人惊讶的是，我们有 现在证明ODC是Myc诱导Cks1转录所必需的。总体而言，这些发现表明 MYC&GT；ODC&GT；Cks1-to-p27Kip1通路驱动Myc诱导的增殖和肿瘤的发生。使用经过验证的 MYC驱动的小鼠B细胞淋巴瘤和乳腺癌模型以及K-RAS导向的肺模型 腺癌，我们将测试ODC在癌基因驱动的增殖和肿瘤发展中的作用， 维持恶性状态，及其与肿瘤抑制通路的相互作用。这些研究 包括那些评估潜在治疗指数的研究，其中ODC丢失对Pre-Pre的内在影响 现有的肿瘤细胞与其在正常细胞中的作用将被确定。我们还将严格评估 P27Kip1和Cks1作为ODC下游靶点在癌症发生和肿瘤维持中的作用 将定义ODC调节Cks1和p27Kip1表达的机制。鉴于无处不在的 Myc和RAS相关恶性肿瘤在人类癌症中的侵袭性，特别是在这三种肿瘤中 在此询问的恶性肿瘤，以及确定靶向ODC在人类中的有效性的临床试验 对于癌症的化学预防，拟议的研究显然与国家癌症研究所的使命高度相关。

Project Summary The Myc family of oncogenic transcription factors is activated in ~70% of human cancers and they regulate the transcription of a large cast (10-15%) of the genome to coordinate metabolism, cell growth and division, differentiation, and development. Further, Myc lies downstream of activated Ras oncoproteins that are frequently mutated in human cancers, where Ras signaling impairs turnover of Myc protein and augments its transcriptional activity. Over the past funding cycle we demonstrated that Myc's proliferative response is rate limiting for tumor development. Remarkably, this pathway strictly relies on a single Myc transcription target, ornithine decarboxylase (Odc), the rate limiting enzyme of polyamine biosynthesis. Here we demonstrated that treatment with the Odc suicide inhibitor DFMO, or simply halving the levels of Odc (in Odc+/- mice), triples the lifespan of tumor-prone, Myc transgenic mice and that it also impairs epidermal carcinogenesis, which is associated with activating mutations in Ras. Collectively, these findings suggest that targeting Odc will have widespread benefit in cancer prevention, a fact now validated in ongoing human cancer chemoprevention trials. Further, we established that targeting Odc disables Myc's proliferative response by selectively affecting Myc's ability to provoke the degradation of the cyclin- dependent kinase inhibitor p27Kip1, a tumor suppressor that inhibits entry and progression through S-phase. Here we first demonstrated that Myc triggers p27Kip1 degradation by activating the transcription of Cks1, a component of the SCFSkp2 E3 ubiquitin ligase complex that directs p27Kip1 destruction. Surprisingly, we have now shown that Odc is required for Myc to induce Cks1 transcription. Collectively, these findings suggest a Myc>Odc>Cks1-to-p27Kip1 pathway drives Myc-induced proliferation and tumorigenesis. Using validated Myc-driven mouse models of B cell lymphoma and mammary adenocarcinoma, and of K-Ras-directed lung adenocarcinoma, we will test the roles of Odc in oncogene-driven proliferation and tumor development, the maintenance of the malignant state, and its interplay with tumor suppressor pathways. These studies include those that evaluate potential therapeutic index, where the intrinsic effects of Odc loss on pre- existing tumor cells versus its effects in normal cells will be determined. We will also critically assess the roles of p27Kip1 and Cks1 as downstream targets of Odc in cancer development and tumor maintenance, and will define the mechanism by which Odc regulates Cks1 and p27Kip1 expression. Given the pervasive and aggressive nature of Myc- and Ras-associated malignancies in human cancer, especially in the three malignancies interrogated herein, and clinical trials establishing the efficacy of targeting Odc in human cancer chemoprevention, the proposed studies are clearly highly relevant to the mission of the NCI.