The Bcl-2-p85/PI3K signaling axis

描述（由申请人提供）：Bcl-2控制线粒体的程序性细胞死亡（凋亡）途径和从质膜调控细胞存活的PI3K/AKT信号通路。这两种途径都与许多癌症和其他疾病有关。虽然两种途径之间的一些相互作用是显而易见的，但对于癌症和其他疾病的新疗法的可能后果，仍有许多有待了解。Bcl-2的特点是一个大的、天然的非结构化的调节环，作为激活其在线粒体上的促或抗凋亡功能的开关，我们和其他人已经报道过。我们最近发现磷酸肌苷3-激酶（PI3K）的p85a调控亚基也与Bcl-2环相互作用。我们的初步结果表明，在体外和体内，这种相互作用增强了PI3K及其下游激酶AKT（蛋白激酶B）的激活，并且Bcl-2对PI3K/AKT信号的激活可以与其抗凋亡功能分离。在一些癌细胞系中，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Bcl-2环衍生的短肽抑制Bcl-2/p85a相互作用、AKT激活和细胞生长。我们将验证的中心假设是Bcl-2与p85a的相互作用可以通过形成含有活性Bcl-2的PI3K信号体激活PI3K/AKT信号。我们的目标是使用综合多学科方法来解决有关Bcl-2/p85相互作用的几个问题：1)。体外和体内研究中，Bcl-2与p85a的相互作用是否有助于癌细胞中PI3K/AKT信号的升高？2）. p85a是如何与Bcl-2相互作用的，又是如何调控这种相互作用的？3)。我们能否确定基于Bcl-2肽的Bcl-2介导的PI3K/AKT激活的拟肽抑制剂来研究这种新的Bcl-2介导的生存途径？我们提出的研究将揭示一个新的bcl -2介导的癌细胞PI3K/AKT信号通路，该信号通路可能在增强癌细胞存活和对化疗和放疗产生耐药性方面发挥关键作用。我们的研究还可能为开发新型基于Bcl-2的PI3K抑制剂提供线索，用于治疗人类癌症和其他Bcl-2经常过度表达的病变。

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.