Pak1 Signaling and Targets in Breast Cancer Progression

乳腺癌进展中的 Pak1 信号传导和靶点

• 批准号: 8444555
• 负责人: Rakesh Kumar
• 金额: $ 24.01万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-18 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444555
• 关键词: Address; Biological Models; Biology; Breast Cancer Cell; Cancer Patient; Cancer Prognosis; Cell Cycle Progression; Cell Nucleus; Cell Proliferation; Cell surface; Complex; Consensus; DNA; Defect; Distant; E2F1 gene; Ensure; Event; Family; G1/S Transition; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; HSF1; Heat-Shock Response; Human; Invaded; Knowledge; Laboratories; Lead; Mitosis; Mitotic; Molecular; Nuclear; Operative Surgical Procedures; Organ; PLK1 gene; Pathway interactions; Phase Transition; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Play; Polyploidy; Regulation; Research; Research Design; Role; S Phase; Signal Transduction; Site; Testing; Time; Work; innovation; malignant breast neoplasm; mortality; mouse model; new growth; novel; p21-activated kinase 1; prognostic; promoter; transcription factor; tumor progression

DESCRIPTION (provided by applicant): Breast cancer progression is driven by deregulated proliferation, the acquisition of inappropriate invasiveness and mitotic defects, in addition to other phenotypic changes. One molecule known to cause progression of breast cancer cells to more invasive phenotypes is p21-activated kinase 1 (Pak1), a nodular kinase activated by a variety of cell surface or intracellular signals. Despite the remarkable growth of new information on the biology of Pak1 in the last decade, we still do not know how Pak1 participates in essential, regulatory events which ensure S-phase progression and controlled mitosis and how it could significantly influence the status of polyploidy in breast cancer The purpose of this project is to clarify and define for the first time the significant role of signal-dependent stimulation of Pak1 in the G1-to-S transition and in mitotic progression, in both physiological and aberrant cell proliferation. These studies are designed to offer a molecular explanation for the well-documented effect of Pak1 dysregulation at two critical points in cell cycle progression. In addition, we will test the hypothesis that E2F1 and HSF1 transcriptional factors are determinants of Pak1 functions at the G1/S phase transition and during mitosis using functionally relevant, genetic mouse models. And finally, we will evaluate and the prognostic significance of these emerging molecules in breast cancer progression. The rationale for this proposal is drawn from a number of findings from the PI's laboratory supported by R01-CA090970-09, for which we are seeking renewal. These findings to suggest that Pak1 signaling plays an inherent role in controlling the G1-to-S phase transition and mitotic progression via E2F1 or HSF1 respectively, and that E2F1 and HSF1 might be novel determinants of Pak1 functions in breast cancer cells. Our testable hypotheses are: Deregulation of Pak1 signaling stimulates E2F1- and HSF1-dependent pathways; and consequently, deregulation of Pak1 signaling confers deregulated G1-to-S-transition and mitotic progression in breast cancer cells. To address these hypotheses, our Specific Aims are to: To address these hypotheses, our Specific Aims are to: (1) Investigate the mechanism by which Pak1 regulates the G1-to-S progression by defining the impact of Pak1-phosphorylation upon the functions of E2Fs; (2) Determine the role of HSF1 in the nuclear accumulation of activated Pak1 and in mitotic progression of breast cancer cells; and (3) To study the role of E2F1 or HSF1 as determinant of Pak1 function in the G1/S transition and mitotic progression in physiological relevant model systems. Our proposed research is significant as the knowledge gained here may reveal Pak1 signaling-dependent regulation of the E2F family and HSF1 transcriptional factors for the first time, and thus, defining novel Pak1 functions in the G1-to-S-transition and mitotic progression of breast cancer cells. Additionally, this work is innovative because we will start understanding the principles by which Pak1 regulates transcription of a subset of genes with roles in the S-phase and mitosis.

描述（由申请人提供）：除其他表型变化外，乳腺癌的进展是由放松管制的增殖，不当侵入性和有丝分裂缺陷驱动的。一种已知会导致乳腺癌细胞进展到更具侵入性表型的分子是P21激活的激酶1（PAK1），这是一种由多种细胞表面或细胞内信号激活的结节性激酶。尽管过去十年中有关PAK1生物学的新信息的显着增长，但我们仍然不知道PAK1如何参与必不可少的监管事件，这些事件确保了S期的进展和受控的有丝膜，以及它如何显着影响多倍性在乳腺癌中多倍性的状态，该项目的目的是澄清并定义了PREDISS的首次启动，并在Pake的启动中定义了Pak1的重要作用，而Pak1 of Pake则涉及PAK1的重要作用。生理和异常细胞增殖。这些研究旨在为PAK1失调在细胞周期进程中两个临界点上有据可查的作用提供分子解释。此外，我们将测试以下假设：E2F1和HSF1转录因子是G1/S相变的PAK1函数的决定因素以及使用功能相关的遗传小鼠模型在有丝分裂期间。最后，我们将评估这些新兴分子在乳腺癌进展中的预后意义。该提案的基本原理是从R01-CA090970-09支持的PI实验室的许多发现中得出的，我们正在寻求续订。这些发现表明，PAK1信号在通过E2F1或HSF1分别控制G1-S相变和有丝分裂进程方面起着固有的作用，并且E2F1和HSF1可能是PAK1在乳腺癌细胞中功能的新型决定因素。我们可检验的假设是：PAK1信号传导的放松管制刺激E2F1-和HSF1依赖性途径；因此，PAK1信号传导的放松管制赋予了乳腺癌细胞中的G1至S-转变和有丝分裂进展。为了解决这些假设，我们的具体目的是：解决这些假设，我们的具体目的是：（1）研究PAK1通过定义PAK1-磷酸化对E2FS功能的影响来调节G1-to-s进展的机制； （2）确定HSF1在活化PAK1的核积累以及乳腺癌细胞的有丝分裂进展中的作用； （3）研究E2F1或HSF1作为PAK1功能在G1/S型中的决定因素和生理相关模型系统中的有丝分裂进程的作用。我们提出的研究很重要，因为这里获得的知识可能揭示了首次对E2F家族和HSF1转录因子的PAK1信号传导依赖性调节，因此，定义了新型PAK1在G1至S-S-S-S-S--S-转化和有丝分裂进展中的作用。此外，这项工作具有创新性，因为我们将开始理解PAK1调节在S期和有丝分裂中具有作用的基因子集的转录的原理。