Phospholipase D-mTOR survival signals in tumorigenesis

描述（由申请人提供）：默认凋亡程序已被改编为对抗癌症的第一道防线，并且几乎所有癌细胞都具有激活“存活信号”以抑制凋亡的突变。存活信号传导的中心节点是mTOR（雷帕霉素的哺乳动物靶标）。mTOR响应于由磷脂酰肌醇-3-激酶（PI 3 K）信号传导途径介导的信号而被激活。然而，最近已经变得明显的是，mTOR也被激活磷脂酶D（PLD）的信号靶向。PLD产生磷脂酸（PA），一种脂质第二信使，其以与雷帕霉素竞争的方式直接与mTOR相互作用，并且PA是mTOR激活所需的。重要的是，PLD活性在几种类型的人类癌症中升高。PLD活性在许多人类癌细胞中升高，并且是mTOR介导的信号所必需的，所述mTOR介导的信号对于存活和促进细胞周期进展至关重要。该提案的中心假设是-人类癌细胞中PLD活性升高促进通过晚期G1“细胞生长检查点”并抑制默认凋亡程序。我们认为，几乎所有的癌细胞都必须激活信号，才能通过这个检查点。具体而言，我们建议：1）确定PLD-mTOR信号传导如何通过提出的细胞生长检查点影响细胞周期进程; 2）确定PLD产生的PA与其他信号传导输入协同调节mTORC 1和mTORC 2的机制; 3）表征导致人类癌细胞系中PLD活性升高的信号，并在体外和体内评估靶向这些信号。我们提出，人癌细胞中的PLD-mTOR信号通路代表了癌细胞广泛采用的促进细胞周期进展和抑制默认凋亡程序的策略。这里提出的研究将提供一个框架的合理目标的明显大量的癌症，依赖于PLD活性升高的G1细胞周期的进展和抑制细胞凋亡。

DESCRIPTION (provided by applicant): Default apoptotic programs have been adapted as a first line of defense against cancer, and virtually all cancer cells have mutations that activate "survival signals" in order to suppress apoptosis. A central node in survival signaling is mTOR (the mammalian target of rapamycin). mTOR is activated in response to signals mediated by the phosphatidylinositol-3-kinase (PI3K) signaling pathway. However, more recently it has become apparent that mTOR is also targeted by signals that activate phospholipase D (PLD). PLD generates phosphatidic acid (PA), a lipid second messenger that interacts directly with mTOR in a manner that is competitive with rapamycin - and PA is required for the activation of mTOR. Importantly, PLD activity is elevated in several types of human cancer. PLD activity is elevated in many human cancer cells and is required for mTOR-mediated signals that are critical for survival and promote cell cycle progression. The CENTRAL HYPOTHESIS of the proposal is - Elevated PLD activity in human cancer cells promotes passage through a late G1 "Cell Growth Checkpoint" and suppresses default apoptotic programs. We are proposing that virtually all cancer cells must activate signals that allow passage through this checkpoint. SPECIFICALLY, we propose: 1) To determine how PLD-mTOR signaling impacts on cell cycle progression through a proposed Cell Growth Checkpoint; 2) To determine the mechanism by which PLD-generated PA regulates mTORC1 and mTORC2 in concert with other signaling inputs; and 3) To characterize signals that lead to elevated PLD activity in human cancer cell lines and to evaluate targeting these signals pharmacologically both in vitro and in vivo. We are proposing that a PLD-mTOR signaling pathway in human cancer cells represents a widely employed strategy by cancer cells to promote cell cycle progression and suppress default apoptotic programs. The studies proposed here will provide a framework for the rational targeting of an apparent large number of cancers that depend upon elevated PLD activity for G1 cell cycle progression and suppression of apoptosis.