Pak1 Signaling and Targets in Breast Cancer Progression

描述（由申请人提供）：乳腺癌的进展是由增殖失控、获得不适当的侵袭性和有丝分裂缺陷以及其他表型变化驱动的。一个已知导致乳腺癌细胞向更具侵袭性表型进展的分子是p21活化激酶1 (Pak1)，这是一种由多种细胞表面或细胞内信号激活的结节激酶。尽管在过去的十年中，关于Pak1生物学的新信息显著增长，但我们仍然不知道Pak1如何参与确保s期进展和控制有丝分裂的重要调控事件，以及它如何显著影响乳腺癌多倍体的状态。本项目的目的是首次阐明和定义信号依赖性刺激Pak1在g1到s转变和有丝分裂过程中的重要作用。在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的两个关键点上的作用提供分子解释。此外，我们将使用功能相关的遗传小鼠模型验证E2F1和HSF1转录因子在G1/S期和有丝分裂期间是Pak1功能的决定因素的假设。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。该建议的基本原理来自PI实验室的一些发现，这些发现得到了R01-CA090970-09的支持，我们正在寻求更新。这些发现表明Pak1信号分别通过E2F1或HSF1在g1 - s期转变和有丝分裂过程中发挥着内在作用，E2F1和HSF1可能是Pak1在乳腺癌细胞中功能的新决定因素。我们可测试的假设是：Pak1信号的解除刺激E2F1-和hsf1依赖通路；因此，Pak1信号的解除会导致乳腺癌细胞中g1到s转化和有丝分裂过程的解除。为了解决这些假设，我们的具体目标是：(1)通过定义Pak1磷酸化对E2Fs功能的影响来研究Pak1调节g1到s进程的机制；(2)确定HSF1在活化Pak1的核积累和乳腺癌细胞有丝分裂进程中的作用；(3)研究在生理相关模型系统中，E2F1或HSF1作为Pak1功能的决定因素在G1/S转变和有丝分裂过程中的作用。我们提出的研究具有重要意义，因为在这里获得的知识可能首次揭示了Pak1信号依赖性的E2F家族和HSF1转录因子的调控，从而定义了Pak1在乳腺癌细胞g1到s转化和有丝分裂过程中的新功能。此外，这项工作具有创新性，因为我们将开始了解Pak1调节s期和有丝分裂中作用的基因子集的转录的原理。

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. PUBLIC HEALTH RELEVANCE: Despite the remarkable growth of new information on the biology of p21-activated kinase 1 (Pak1) in breast cancer cells, 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.