Pak1 Signaling and Targets in Breast Cancer Progression

描述（由申请方提供）：乳腺癌进展由增殖失调、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。已知导致乳腺癌细胞进展为更具侵袭性表型的一种分子是p21激活激酶1（Pak 1），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Pak 1生物学的新信息显著增长，但我们仍然不知道Pak 1如何参与重要的，确保S期进展和控制有丝分裂的调节事件，以及它如何显著影响乳腺癌中多倍体的状态。本项目的目的是首次澄清和定义信号的重要作用，Pak 1在G1-to-S转换和有丝分裂进程中的依赖性刺激，在生理和异常细胞增殖中。这些研究旨在为Pak 1失调在细胞周期进程中两个关键点的作用提供分子解释。此外，我们将测试的假设，即E2 F1和HSF 1转录因子是决定因素的Pak 1功能在G1/S相变和有丝分裂过程中使用功能相关的，遗传小鼠模型。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。该提案的依据来自R 01-CA 090970 -09支持的PI实验室的许多结果，我们正在寻求更新。这些发现表明Pak 1信号分别通过E2 F1或HSF 1在控制G1-to-S期转变和有丝分裂进程中起着固有的作用，并且E2 F1和HSF 1可能是Pak 1在乳腺癌细胞中功能的新决定因素。我们可检验的假设是：Pak 1信号的失调刺激E2 F1-和HSF 1-依赖性途径;因此，Pak 1信号的失调赋予乳腺癌细胞中G1-到-S-转变和有丝分裂进展的失调。为了解决这些假设，我们的具体目标是：（1）通过确定Pak 1磷酸化对E2 Fs功能的影响，研究Pak 1调节G1到S进程的机制;（2）确定HSF 1在活化的Pak 1的核积累和乳腺癌细胞有丝分裂进程中的作用;（3）在生理相关模型系统中研究E2 F1或HSF 1作为Pak 1功能决定因子在G1/S转换和有丝分裂进程中的作用。我们提出的研究是重要的，因为这里获得的知识可能首次揭示Pak 1信号依赖性调节E2 F家族和HSF 1转录因子，从而定义新的Pak 1功能在乳腺癌细胞的G1到S过渡和有丝分裂进程。此外，这项工作是创新的，因为我们将开始了解Pak 1调节S期和有丝分裂中基因子集转录的原理。

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.