CDK inhibitors in tumor progression

描述（由申请人提供）：cdk抑制剂Kip家族的最佳理解功能是抑制cdk 2并诱导细胞周期退出。我们的实验室还表明，p21在分化、增殖和肿瘤发展中也有作用。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，这可以解释这些蛋白在某些癌症中的作用;然而，任何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-cdk 4的能力可能是重要的发展ODG的PDGF诱导小鼠。为了进一步理解这一点，并解决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。在肿瘤发展过程中的动物与细胞和生物化学研究，概括的PDGF诱导的祖细胞转化的细胞系中的互补研究表明，p21通过稳定细胞周期蛋白D1-cdk 4促进ODG。为了证实这一点，我们建议确定如何调节细胞周期蛋白D1和cdk 4的表达影响肿瘤的进展。此外，将开发小鼠p21基因敲入模型，以在该模型中建立细胞周期蛋白-cdk结合对肿瘤发展的重要性。具体目标2。p21表达与人ODG的不良预后有关;然而，p21状态反映了ODG的性质或治疗患有该疾病的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诱导的细胞周期蛋白D1-cdk 4的稳定化。此外，我们将使用140人ODG收集，以确定是否p21表达与激活PDGF信号通路的特定变化相关，或是否p21状态反映了早期肿瘤细胞如何增加细胞周期蛋白D1-cdk 4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，并且现存的文献表明它不是胶质细胞谱系所独有的。当考虑将p21作为潜在的治疗靶点时，了解p21的生长调节积累将是重要的。在这个目标中，我们将研究转录后机制调节p21，和磷酸化在YH细胞和肿瘤发展过程中发挥的作用。

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.