Role of p300/CBP and hHR23 Proteins in p53 Regulation

p300/CBP 和 hHR23 蛋白在 p53 调节中的作用

• 批准号: 8287740
• 负责人: Steven R. Grossman
• 金额: $ 6.85万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-19 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287740
• 关键词: Adaptor Signaling Protein; Apoptosis; Binding; Binding Proteins; Cells; Cellular Stress; Chemicals; Chromatin; Clinical; Complex; Cytoplasm; DNA Damage; Data; Development; E1A-associated p300 protein; EP300 gene; Enzymes; Family; Feedback; Gap Junctions; Genetic Transcription; Genomics; Goals; Grant; Growth; Homeostasis; Human; Hypoxia; Ionizing radiation; Knowledge; Lead; MDM2 gene; Malignant - descriptor; Malignant Neoplasms; Metabolic Pathway; Metabolism; Monoubiquitination; Mutagens; Mutate; Nuclear; Nutrient; Oncogene Activation; Oncogenic; Pathway interactions; Polyubiquitin; Polyubiquitination; Process; Protein Family; Protein p53; Proteins; Regulation; Role; Signal Transduction; Stress; Structure; Suicide; System; Therapeutic; Tumor Suppressor Proteins; Ubiquitin; Ubiquitination; Work; cancer cell; cell killing; deprivation; multicatalytic endopeptidase complex; novel; programs; public health relevance; research study; response; scaffold; therapeutic target; tumor; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant):The p53 tumor suppressor counters a wide range of stresses, including chemical mutagens, ionizing radiation, hypoxia, and nutrient deprivation, by activating growth arrest or apoptosis programs. All cancers must inactivate the p53 network at one or more of its nodes to progress. Most often, p53 is mutated such that it is inactivated in tumors. In other cases, regulators of p53 are altered instead of p53 itself. Frequently, the regulators that are altered in cancer cells participate in the normal destruction of p53 protein by the ubiquitin/proteasome system. The pathway of p53 destruction by the ubiquitin/proteasome system is complex, involving monoubiquitination, polyubiquitination, recognition by polyubiquitin-binding proteins, and recognition and degradation by the proteasome. p53 is monoubiquitinated by the E3 ligase MDM2, and work from the prior grant has shown that the p300/CBP coactivators are E4 enzymes catalyzing further polyubiquitination of p53 in the cytoplasm. Polyubiquitinated p53 can be recognized by the hHR23 family of proteasome adaptor proteins, which appear to shield p53 from proteasome destruction after cell stress such as DNA damage, but may also normally deliver p53 to the proteasome. hHR23 proteins, in turn, are recognized by the S5a subunit of the proteasome, which may be the gateway to the proteasome for p53, leading to its destruction. The Aims of this renewal application are to: 1. Characterize the structure and function for p53 polyubiquitination of a p300/CBP E4 activity 2. Investigate the role of p300/CBP E4 and Ub binding activities in p53 regulation 3. Investigate the role of hHR23 and S5a in p53 regulation A firm and complete understanding of the pathway of p53 destruction by the ubiquitin/proteasome system will increase our knowledge of how cancers form through disruption of this pathway, and also lead to the development of novel cancer therapeutics targeting this pathway. Such therapeutics hold the hope of reactivating p53 in those tumors harboring wild type p53, leading to the arrest or apoptosis of malignant cells within. PUBLIC HEALTH RELEVANCE: All cancers disrupt the function of a protective protein called p53. Cells normally keep p53 in check until it is needed by manufacturing and immediately destroying it. When it is needed, such as the case when a cell is turning malignant, its destruction is halted and the p53 levels build up. In some tumors, this destruction system is permanently "on" so that p53 cannot be activated to battle the cancer. A firm and complete understanding of the pathway of p53 destruction by the ubiquitin/proteasome system will increase our knowledge of how cancers form through disruption of this pathway, and also lead to the development of novel cancer therapeutics targeting this pathway. Such therapeutics hold the hope of reactivating p53 in those tumors where the p53 destruction pathway is disrupted, leading to the destruction of cancer cells by their own suicide program.

描述（由申请人提供）：p53肿瘤抑制因子通过激活生长停滞或细胞凋亡程序来对抗多种应激，包括化学诱变剂、电离辐射、缺氧和营养缺乏。所有癌症都必须使一个或多个节点的 p53 网络失活才能进展。最常见的是，p53 发生突变，导致其在肿瘤中失活。在其他情况下，p53 的调节因子而不是 p53 本身被改变。通常，癌细胞中改变的调节因子参与泛素/蛋白酶体系统对 p53 蛋白的正常破坏。泛素/蛋白酶体系统破坏p53的途径很复杂，涉及单泛素化、多泛素化、多泛素结合蛋白的识别以及蛋白酶体的识别和降解。 p53 被 E3 连接酶 MDM2 单泛素化，先前资助的工作表明 p300/CBP 共激活剂是 E4 酶，可催化细胞质中 p53 的进一步多泛素化。多泛素化的 p53 可以被蛋白酶体接头蛋白的 hHR23 家族识别，该家族似乎可以保护 p53 在细胞应激（例如 DNA 损伤）后免受蛋白酶体破坏，但也可以正常地将 p53 传递到蛋白酶体。 hHR23 蛋白反过来被蛋白酶体的 S5a 亚基识别，这可能是 p53 通往蛋白酶体的门户，导致其被破坏。本次更新申请的目的是： 1. 表征 p300/CBP E4 活性的 p53 多泛素化的结构和功能 2. 研究 p300/CBP E4 和 Ub 结合活性在 p53 调节中的作用 3. 研究 hHR23 和 S5a 在 p53 调节中的作用 牢固、完整地了解泛素/蛋白酶体系统破坏 p53 的途径 将增加我们对如何通过破坏该途径形成癌症的了解，并导致针对该途径的新型癌症疗法的开发。此类疗法有望在那些含有野生型 p53 的肿瘤中重新激活 p53，从而导致内部恶性细胞的停滞或凋亡。 公共健康相关性：所有癌症都会破坏一种名为 p53 的保护性蛋白质的功能。细胞通常会控制 p53，直到制造需要它并立即销毁它。当需要时，例如当细胞发生恶性时，其破坏就会停止，p53 水平就会升高。在某些肿瘤中，这种破坏系统永久“开启”，因此 p53 无法被激活来对抗癌症。对泛素/蛋白酶体系统破坏 p53 的途径的深入而完整的了解将增加我们对癌症如何通过破坏该途径形成的了解，并导致针对该途径的新型癌症治疗方法的开发。这种疗法有望在 p53 破坏途径被破坏的肿瘤中重新激活 p53，从而导致癌细胞通过自身的自杀程序被破坏。