The Bcl-2-p85/PI3K signaling axis

描述（由申请人提供）：Bcl-2控制线粒体上的程序性细胞死亡（凋亡）途径和从质膜调节细胞存活的PI 3 K/AKT信号传导途径。这两种途径都与许多癌症和其他疾病有关。虽然这两种途径之间的一些串扰是显而易见的，但仍有许多问题需要了解，这些问题可能会对癌症和其他疾病的新疗法产生影响。Bcl-2的特点是一个大的，天然非结构化的，调节环，作为一个开关，激活其促或抗线粒体凋亡的功能，我们和其他人已经报道。我们最近发现磷酸肌醇3-激酶（PI 3 K）的p85 a调节亚基也与Bcl-2环相互作用。我们的初步研究结果表明，相互作用增强激活PI 3 K及其下游激酶AKT（蛋白激酶B）在体外和体内，并认为激活PI 3 K/AKT信号由Bcl-2可以从其抗凋亡功能分离。在几种癌细胞系中，Bcl-2表达增强基础和生长因子诱导的AKT活化。我们还发现来源于Bcl-2环的短肽抑制Bcl-2/p85 a相互作用、AKT活化和细胞生长。我们将检验的中心假设是Bcl-2与p85 a的相互作用可以通过形成含有活性Bcl-2的PI 3 K信号体来激活PI 3 K/AKT信号传导。我们的目标是使用综合的多学科方法来解决有关Bcl-2/p85相互作用的几个问题：1）。Bcl-2与p85 a的相互作用是否有助于体外和体内癌细胞中PI 3 K/AKT信号的升高？2）。p85 a如何与Bcl-2相互作用以及相互作用如何调节？3）。我们能否鉴定Bcl-2肽基拟肽抑制剂Bcl-2介导的PI 3 K/AKT活化，用于研究这种新的Bcl-2介导的生存途径？我们提出的研究将揭示癌细胞中一种新的Bcl-2介导的PI 3 K/AKT信号通路，这可能在增强癌细胞的存活率及其对化疗和放疗的抵抗力方面发挥关键作用。我们的研究也可能导致开发新的基于Bcl-2的PI 3 K抑制剂用于治疗人类癌症和Bcl-2经常过表达的其他病变的线索的鉴定。

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.