Regulation of pten tumor suppressive functions by C-tail phosphorylation.

通过 C 尾磷酸化调节 pten 肿瘤抑制功能。

• 批准号: 9810636
• 负责人: Darren Baker
• 金额: $ 36.37万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-02 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9810636
• 关键词: AKT Signaling Pathway; Advanced Malignant Neoplasm; Alanine; Alleles; Antineoplastic Agents; Binding; Biological; Biological Process; Cancer Biology; Cancer Patient; Cells; Clinical; Cultured Cells; Development; Embryonic Development; Enzymes; Foundations; Generations; Genetically Engineered Mouse; Goals; Homo; Human; Hyperactive behavior; In Vitro; Individual; Knock-out; Knowledge; Lesion; Loss of Heterozygosity; Lymphatic Diseases; Malignant Neoplasms; Mammary gland; Molecular Conformation; Monitor; Mouse Strains; Mus; Mutant Strains Mice; Mutate; Mutation; Neoplastic Cell Transformation; Nuclear; Outcome; PDPK1 gene; PTEN gene; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Physiology; Post-Translational Protein Processing; Predisposition; Property; Prostate; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Role; Series; Serine; Signal Transduction; Systems Biology; Tail; Testing; Threonine; Tissues; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; base; cohort; comparative; improved; in vivo; innovation; insight; mouse development; mouse model; mutant; neoplastic; novel therapeutic intervention; preservation; treatment strategy; tumor; tumorigenesis

PROJECT SUMMARY/ABSTRACT Pten is a prominent tumor suppressor whose tumor protective ability is exquisitely sensitive to alterations in level of expression or activity. This property has led to speculation that mechanisms controlling Pten expression, sta- bility, conformation, homo- and heterotypic protein interactions, localization, or catalytic activity, including post- translational modifications, are prominent targets for deregulation in human cancer. However, this concept has not been critically tested at the organismal level, mainly because of difficulty in manipulating Pten in mice due to its essential role in embryogenesis. Our long-term objective is to close this knowledge gap by the use of mouse models in which specific Pten domains or regulatory mechanisms are inactivated and to apply the information gained to develop innovative strategies for the treatment of human cancers with Pten alterations. As the next step in the pursuit of this goal, our objective here is to understand, at the physiological level, how the phosphor- ylation status of the C-tail region regulates Pten. Based on extensive preliminary studies, we hypothesize that individual C-tail serine/threonine residues differentially regulate the stability, localization, interactome and/or phosphatase activity of Pten in vivo, thereby impacting its tumor suppressive functions in both Akt-dependent and -independent fashions. We propose to test this hypothesis by pursuing two specific aims. In the first aim, we will comprehensively examine tissues and cultured cells from a core set of eight nonphosphorylatable and phos- phomimetic C-tail mutant mice for changes in Pten biological properties and functions. In the second aim, we will monitor these same mouse strains alongside cohorts of wildtype, Pten hypomorphic and Pten+/– mice for the development of spontaneous tumors, with emphasis on prostate and mammary gland lesions. Additionally, we will conduct a comparative analysis of pre-tumorous and tumorous tissues of these strains for alterations in Pten properties and functions. By completing these aims, we expect to gain insight into the properties of these C-tail mutants in physiologically relevant settings with regards to protein stability, localization, catalytic activity and binding partners, and to integrate these findings with information about the biological and tumor suppressive functions that these mutants have lost, preserved, or gained. The expected overall impact of this innovative proposal is that it will fundamentally advance our mechanistic understanding of the normal and neoplastic func- tions of the second most frequently mutated tumor suppressor gene in human cancer. This knowledge will con- ceptually advance the cancer biology field, improve our understanding of the Akt signaling pathway in normal physiology and cancer, and lay the foundation for the development of new therapeutic strategies that will improve the clinical outcome of cancer patients with alterations in Pten.

项目概要/摘要 Pten 是一种重要的肿瘤抑制因子，其肿瘤保护能力对水平的变化非常敏感 这一特性导致人们推测控制 Pten 表达、sta- 的机制。 能力、构象、同型和异型蛋白质相互作用、定位或催化活性，包括后 翻译修饰是人类癌症放松管制的重要目标。 尚未在生物学水平上进行严格的测试，主要是因为在小鼠体内操纵 Pten 很困难，因为 我们的长期目标是通过使用小鼠来缩小这一知识差距。 特定 Pten 域或监管机制失活的模型并应用该信息 获得通过 Pten 改变开发治疗人类癌症的创新策略。 为了实现这一目标，我们的目标是在生理水平上了解磷光体如何 基于广泛的初步研究，我们认为 C 尾区的化状态调节 Pten。 各个C尾丝氨酸/苏氨酸残基差异调节稳定性、定位、相互作用组和/或 Pten 体内磷酸酶活性，从而影响其在 Akt 依赖性肿瘤抑制功能 我们建议通过追求两个具体目标来检验这一假设。 将全面检查来自八个非磷酸化和磷酸化核心组的组织和培养细胞 拟似 C 尾突变小鼠 Pten 生物学特性和功能的变化 在第二个目标中，我们。 将监测这些相同的小鼠品系以及野生型、Pten 亚型和 Pten+/– 小鼠群体 自发性肿瘤的发展，重点是前列腺和乳腺病变。 将对这些菌株的肿瘤前组织和肿瘤组织进行 Pten 改变的比较分析 通过完成这些目标，我们期望深入了解这些 C-tail 的属性。 突变体在生理相关环境中的蛋白质稳定性、定位、催化活性和 结合伙伴，并将这些发现与有关生物和肿瘤抑制的信息相结合 这些突变体失去、保留或获得的功能这一创新的预期总体影响。 建议是，它将从根本上增进我们对正常和肿瘤功能的机械理解。 这一知识将证明人类癌症中第二常见突变的肿瘤抑制基因。 从概念上推进癌症生物学领域，提高我们对正常情况下 Akt 信号通路的理解 生理学和癌症，并为开发新的治疗策略奠定基础，从而改善 Pten 改变的癌症患者的临床结果。