The Bcl-2-p85/PI3K signaling axis

描述(申请人提供)：bcl2控制线粒体上的程序性细胞死亡(凋亡)通路和PI3K/AKT信号通路，后者从质膜调节细胞生存。这两种途径都与许多癌症和其他疾病有关。虽然这两条途径之间的一些串扰是显而易见的，但仍有许多事情需要了解，以及癌症和其他疾病的新疗法可能产生的后果。正如我们和其他人所报道的那样，bcl-2的特征是一个巨大的、天然的非结构化调控环，它是激活其在线粒体上促或抗凋亡功能的开关。我们最近发现，磷脂酰肌醇3-激酶(PI3K)的p85a调节亚基也与Bcl2环相互作用。我们的初步结果表明，这种相互作用在体外和体内都增强了PI3K及其下游蛋白激酶AKT(蛋白激酶B)的激活，而Bcl2对PI3K/AKT信号的激活可能与其抗凋亡功能无关。在几种癌细胞系中，Bcl-2的表达增强了基础和生长因子诱导的AKT激活。我们还发现，从Bcl2环衍生的短肽抑制了Bcl2/p85a相互作用、AKT激活和细胞生长。我们将检验的中心假设是，Bcl2与p85a的相互作用可以通过形成一个含有PI3K信号小体的活性Bcl2来激活PI3K/AKT信号。我们的目标是使用综合的多学科方法来解决与Bcl-2/P85相互作用有关的几个问题：1)。在体内外癌细胞中，Bcl2与p85a的相互作用是否促进了PI3K/AKT信号的升高？P85a是如何与Bcl2相互作用的，这种相互作用是如何调节的？为了研究这一新的Bcl2介导的生存途径，我们能否找到以Bcl2多肽为基础的PI3K/AKT激活的模拟多肽抑制剂？我们提出的研究将在癌细胞中解开一个新的由Bcl2介导的PI3K/AKT信号通路，它可能在提高癌细胞的存活和对化疗和放射治疗的耐药性方面发挥关键作用。我们的研究还可能为开发新型的基于Bcl2的PI3K抑制剂提供线索，用于治疗人类癌症和其他Bcl2高表达的病变。 公共卫生相关性：我们建议研究Bcl2与p85a的相互作用在介导癌细胞中PI3K/AKT激活中的作用及其潜在的分子机制。我们提出的研究有望在癌细胞中确定一个重要的新的生存信号通路，这可能成为一个新的药物靶点。

DESCRIPTION (provided by applicant): Bcl-2 controls programmed cell death (apoptosis) pathway on mitochondria and the PI3K/AKT signaling pathway which regulates cell survival from the plasma membrane. Both pathways have been implicated in many cancers and other diseases. While some crosstalk between the two pathways is apparent, much remains to be understood with likely consequences for novel therapeutics for cancer and other diseases. Bcl-2 is characterized by a large, natively unstructured, regulatory loop that serves as a switch for activating its pro- or anti-apoptotic functions on mitochondria as we and others have reported. We recently discovered that the p85a regulatory subunit of phosphoinositide 3-kinase (PI3K) also interacts with the Bcl-2 loop. Our preliminary results demonstrate that the interaction enhances activation of PI3K and its downstream kinase AKT (protein kinase B) in vitro and in vivo and that the activation of PI3K/AKT signaling by Bcl-2 can be dissociated from its anti-apoptotic function. In several cancer cells lines, Bcl-2 expression enhances both basal and growth factor-induced AKT activation. We also found that short peptides derived from the loop of Bcl-2 inhibit Bcl-2/p85a interaction, AKT activation, and cell growth. The central hypothesis we will test is that Bcl-2 interaction with p85a can activate PI3K/AKT signaling by forming an active Bcl-2-containing PI3K signalosome. Our objectives are to use integrated multidisciplinary approaches to address several issues regarding the Bcl-2/p85 interaction: 1). Does Bcl-2 interaction with p85a contribute to elevated PI3K/AKT signaling in cancer cells in vitro and in vivo? 2). How does p85a interact with Bcl-2 and how is the interaction regulated? 3). Can we identify Bcl-2 peptide-based peptidomimetic inhibitors of Bcl-2-mediated PI3K/AKT activation for studying this new Bcl-2-mediated survival pathway? Our proposed studies will unravel a new Bcl-2-mediated PI3K/AKT signal pathway in cancer cells, which likely plays a critical role in enhancing the survival of cancer cells and the development of their resistance to chemo and radiation therapies. Our studies may also result in the identification of leads for developing novel Bcl-2-based PI3K inhibitors for treating human cancer and other lesions where Bcl-2 is often overexpressed. PUBLIC HEALTH RELEVANCE: We propose to study the role of Bcl-2 interaction with p85a in mediating the activation of PI3K/AKT in cancer cells and the underlying molecular mechanisms. Our proposed studies are anticipated to identify an important new survival signaling pathway in cancer cells, which may serve as a new drug target.