Structural Analysis of Cancerous Inhibitor of PP2A (CIP2A)

PP2A 癌抑制剂 (CIP2A) 的结构分析

• 批准号: 9282805
• 负责人: Wenqing Xu
• 金额: $ 16.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282805
• 关键词: Adult; Adverse effects; Affinity; Binding; Biochemical; Biological Assay; C-terminal; Cancer Biology; Cancerous; Cells; Coiled-Coil Domain; Colon Carcinoma; Complex; Crystallization; Disease; Drug Targeting; E2F1 gene; Foundations; Frequencies; Future; Goals; Head and Neck Squamous Cell Carcinoma; Hot Spot; Human; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Maps; Measurement; Methods; Mus; Mutagenesis; Mutation; Oncogenes; Oncogenic; Oncoproteins; Patients; Phosphorylation; Protein Phosphatase 2A Regulatory Subunit PR53; Protein Phosphatase Inhibitor; Proteins; Rest; Sampling; Site; Solid; Structural Models; Structure; Surface; System; Tumor Suppressor Proteins; Ubiquitin; Work; X-Ray Crystallography; base; c-myc Genes; cancer cell; cancer therapy; cancer type; cell growth; drug discovery; in vivo; inhibitor/antagonist; insight; malignant breast neoplasm; malignant stomach neoplasm; multicatalytic endopeptidase complex; novel strategies; overexpression; prevent; stoichiometry; targeted cancer therapy; three dimensional structure; transcription factor; tumor; tumorigenesis

Summary Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A), the protein encoded by the oncogene KIAA1524, inhibits the tumor suppressor activity of PP2A in human malignancies. CIP2A overexpression has been found in over 70% of tumor patient samples in the majority of human malignancies, including human head and neck squamous cell carcinoma, colon cancer, gastric cancer, breast cancer, prostate cancer and lung cancer. This makes CIP2A one of the most frequently overexpressed oncoproteins in all cancers. It has been shown that CIP2A is required for the malignant cellular growth and for in vivo tumor formation, by inhibiting PP2A's tumor suppressor activities towards several oncoproteins, including the oncogenic transcription factor c- Myc. Since it is non-essential for adult cells but required for tumoregenesis, CIP2A has become a highly significant drug target for cancer therapy. Knowing the 3D structure of CIP2A is essential for understanding how CIP2A functions and how to develop CIP2A inhibitors for cancer treatment. In this proposal, we aim to determine the first crystal structure of CIP2A and to reveal how it interacts with the regulatory B56 subunit of PP2A.

总结 蛋白磷酸酶2A（CIP 2A）的癌症抑制剂，由 癌基因KIAA 1524抑制人PP 2A的抑癌活性 恶性肿瘤在70%以上的肿瘤患者中发现CIP 2A过表达 大多数人类恶性肿瘤（包括人类头颈部）的样本 鳞状细胞癌、结肠癌、胃癌、乳腺癌、前列腺癌 和肺癌。这使得CIP 2A成为最频繁过表达的细胞之一。 所有癌症中的癌蛋白已经表明，CIP 2A是恶性肿瘤所必需的。 细胞生长和体内肿瘤形成，通过抑制PP 2A的肿瘤抑制因子 对几种癌蛋白的活性，包括致癌转录因子c- Myc由于CIP 2A对成体细胞不是必需的，但对肿瘤发生是必需的，因此CIP 2A具有 成为癌症治疗的一个非常重要的药物靶标。了解3D结构 CIP 2A对于理解CIP 2A如何发挥作用以及如何开发CIP 2A至关重要 用于癌症治疗的抑制剂。在这个提议中，我们的目标是确定第一个晶体 CIP 2A的结构，并揭示它如何与调节B56亚基相互作用， PP2A.