Mechanisms of p27Kipl Proteolysis in Cancer Cells

描述(申请人提供)：由于过度降解，细胞周期抑制物p27Kip1水平降低，出现在各种侵袭性人类肿瘤中。由于在许多人类癌症中，p27的表达降低与预后不良和某些抗肿瘤治疗的抵抗有关，因此人们推测p27的表达升高可以改善预后，甚至可能为恶性肿瘤提供治疗。然而，这一概念尚未得到证实或严格测试，这主要是因为缺乏干扰p27水平异常降低的特定小分子抑制剂。P27的丰度主要受依赖于ATP的泛素-蛋白酶体途径控制。SCFSkp2是降解p27的主要泛素E3连接酶。因此，抑制SCFSkp2 E3连接酶的活性有望促进p27的积累。这项应用的总体目标是研究SCFSkp2 E3连接酶受化学干扰的独特酶机制，并开发用于化学遗传学分析SCFSkp2在癌症生物学中功能的特异性试剂。了解SCFSkp2促进p27泛素化的详细而独特的机制，对于开发高选择性的治疗策略，以最小的副作用提高p27水平至关重要。确定p27降解的特定小分子抑制剂是评估抑制p27降解是否将是有效的抗癌治疗方法的第一步，并将我们所了解的p27降解的基本机制转化为癌症生物学中潜在的新药导向。公共卫生相关性：原发癌组织中过度降解的肿瘤抑制蛋白p27与较低的存活率以及对化疗的较差反应有关。这项提议的目标是了解与异常降解相关的分子过程，并寻找类似药物的分子来防止这种降解。我们的研究可能为恶性肿瘤提供新的治疗方法，并改善侵袭性肿瘤患者的预后。

DESCRIPTION (provided by applicant): Decreased levels of cell cycle inhibitor p27Kip1 due to excessive degradation occur in a variety of aggressive human tumors. Since reduced p27 expression has been associated with a poor prognosis in many human cancers and resistance to certain anti-tumor therapies, it has been postulated that elevation of p27 expression could improve prognosis and perhaps even provide a cure for malignant cancers. However, this concept has not been proven or rigorously tested largely due to the absence of specific small molecule inhibitors that perturb abnormal reduction in p27 levels. The abundance of p27 is primarily controlled by the ATP-dependent ubiquitin-proteasome pathway. SCFSkp2 is the major ubiquitin E3 ligase responsible for degradation of p27. Therefore inhibition of SCFSkp2 E3 ligase activity is expected to enhance p27 accumulation. The overall goals of this application are to investigate unique enzymatic mechanisms of SCFSkp2 E3 ligase that are amenable to chemical perturbation and develop specific reagents for chemical genetic dissection of the function of SCFSkp2 in cancer biology. Understanding the detailed and unique mechanism by which SCFSkp2 promotes ubiquitination of p27 is essential for developing highly selective therapeutic strategies to increase p27 levels with minimal side effects. Identifying specific small molecule inhibitors of p27 degradation is a first step towards evaluating whether inhibition of p27 degradation would be an effective anti-cancer therapy approach and translating what we have learned about the basic mechanisms of p27 degradation into potential new drug leads in cancer biology. PUBLIC HEALTH RELEVANCE: Excessive degradation tumor suppressing protein p27 in primary cancer tissue correlates with poor survival as well as poor response to chemotherapies. The goal of this proposal is to understand the molecular processes associated with abnormal degradation and search for drug-like molecules to prevent this degradation. Our studies could lead to novel therapy for malignant cancers and improve prognosis of patient with aggressive tumors.