CDK inhibitors in tumor progression

CDK抑制剂在肿瘤进展中的作用

• 批准号: 7912564
• 负责人: ANDREW KOFF
• 金额: $ 34.76万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912564
• 关键词: Address; Affect; Animals; Binding; Biochemical; Breast; Cancerous; Cell Cycle; Cell Line; Cell Maintenance; Cell Nucleus; Cell Proliferation; Cells; Clinical; Collection; Complex; Cyclin D1; Cyclin-Dependent Kinases; Cyclins; Data; Development; Disease; Family; Family member; Genetic; Gliomagenesis; Goals; Growth; Growth Factor; Human; Indium; Knock-in Mouse; Laboratories; Literature; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of thyroid; Messenger RNA; Modeling; Molecular; Mus; Mutation; Nature; Nuclear; Oncogenes; PDGF Signaling Pathway; PTK787; Patients; Phosphorylation; Platelet-Derived Growth Factor; Play; Process; Prostate; Proteins; Regulation; Role; Sampling; Signal Transduction; Squamous cell carcinoma; Stem cells; Therapeutic; Translations; cell type; growth promoting activity; human disease; in vivo; inhibitor/antagonist; insight; interest; mouse model; mutant; neoplastic cell; oligodendroglioma; outcome forecast; research study; stem; therapeutic target; tumor; tumor progression

DESCRIPTION (provided by applicant): The best-understood function of the Kip family of cdk inhibitors is to inhibit cdk2 and induce cell cycle exit. Our laboratory also showed that p21 also has roles in differentiation, proliferation and tumor development. Furthermore, p21 accumulation is associated with poor prognosis in oligodendroglioma, squamous cell carcinoma, tall cell thyroid cancer, and some breast, prostate and cervical cancers in humans. p21 can interact with a number of non-cyclin-cdk proteins which might explain the role of these proteins in some cancers; however, the significance of any interaction in vivo to tumor development has not been determined. Our preliminary data demonstrates that the ability of p21 to stabilize cyclin D1-cdk4 may be important for the development of ODG induced by PDGF in mice. To understand this further and address its significance in human disease we propose three aims: Specific aim 1. Complementation studies in animals during tumor development with cellular and biochemical studies in cell lines that recapitulate the PDGF-induced transformation of progenitor cells suggest that p21 promotes ODG by stabilizing cyclin D1-cdk4. To confirm this, we propose to determine how modulating cyclin D1 and cdk4 expression affects tumor progression. Furthermore, a mouse p21 knock-in model will be developed to establish the importance of cyclin-cdk binding for tumor development in this model. Specific aim 2. p21 expression is related to poor prognosis in human ODG; however, what p21 status reflects about the nature of ODG or the ability to treat patients with the disease is not clear. To address this, we will determine if mouse ODG induced by either other oncogenes or from other progenitor cells is also dependent on p21 induced stabilization of cylcin D1-cdk4. In addition, we will use a 140 human ODG collection to determine whether p21 expression correlates with specific changes activating the PDGF signaling pathway or whether p21 status is reflecting differences in how the incipient tumor cells increase the expression of cyclin D1-cdk4. Specific aim 3. We understand the process by which cki accumulate during growth arrest, but know nothing about how they accumulate as cells enter the cell cycle. Our data in ODG support the significance of such regulation, and the extant literature shows that it is not unique to the glial lineage. An understanding of growth-regulated accumulation of p21 will be important when considering this as a potential therapeutic target. In this aim, we will examine the post-transcriptional mechanisms regulating p21, and the role that phosphorylation plays in YH cells and during tumor development.

描述（由申请人提供）： cdk 抑制剂 Kip 家族最了解的功能是抑制 cdk2 并诱导细胞周期退出。我们的实验室还表明p21还在分化、增殖和肿瘤发展中发挥作用。此外，p21 积累与人类少突胶质细胞瘤、鳞状细胞癌、高细胞甲状腺癌以及一些乳腺癌、前列腺癌和宫颈癌的不良预后相关。 p21 可以与许多非细胞周期蛋白-cdk 蛋白相互作用，这可能解释了这些蛋白在某些癌症中的作用；然而，体内相互作用对肿瘤发展的重要性尚未确定。我们的初步数据表明，p21 稳定细胞周期蛋白 D1-cdk4 的能力可能对于 PDGF 诱导的小鼠 ODG 的发育很重要。为了进一步了解这一点并阐述其在人类疾病中的重要性，我们提出了三个目标： 具体目标 1. 在动物肿瘤发展过程中进行的补充研究，以及在细胞系中进行的细胞和生化研究，概括了 PDGF 诱导的祖细胞转化，表明 p21 通过稳定细胞周期蛋白 D1-cdk4 来促进 ODG。为了证实这一点，我们建议确定调节细胞周期蛋白 D1 和 cdk4 表达如何影响肿瘤进展。此外，还将开发小鼠 p21 敲入模型，以确定细胞周期蛋白-cdk 结合对于该模型中肿瘤发展的重要性。具体目标2. p21表达与人ODG不良预后相关；然而，p21 状态如何反映 ODG 的性质或治疗该疾病患者的能力尚不清楚。为了解决这个问题，我们将确定由其他癌基因或其他祖细胞诱导的小鼠 ODG 是否也依赖于 p21 诱导的 cylcin D1-cdk4 稳定。此外，我们将使用 140 个人类 ODG 集合来确定 p21 表达是否与激活 PDGF 信号通路的特定变化相关，或者 p21 状态是否反映了早期肿瘤细胞如何增加细胞周期蛋白 D1-cdk4 表达的差异。具体目标3.我们了解cki在生长停滞期间积累的过程，但对它们在细胞进入细胞周期时如何积累一无所知。我们在 ODG 中的数据支持这种调节的重要性，并且现有文献表明它并不是神经胶质谱系所独有的。当将 p21 视为潜在的治疗靶点时，了解 p21 的生长调节积累非常重要。为此，我们将研究调节 p21 的转录后机制，以及磷酸化在 YH 细胞和肿瘤发展过程中的作用。