Regulation of NF-kB by the Akt kinase

描述(申请人提供)：核因子-？B家族转录因子是基因转录的关键调控因子。现已知，核因子-βB途径的突变有助于细胞转化和癌症的发展。我一直在研究丝氨酸/苏氨酸激酶Akt在细胞激活和核因子？B诱导中的作用。有趣的是，Akt也是一种原癌基因，在癌症中经常被扩增或激活。已知AKT参与包括核因子-βB在内的许多下游通路的激活。I假设核因子-βB的激活在Akt对T细胞激活和转化的影响中起重要作用。目前，核因子-βB在Akt介导的转录上调中的整体作用尚不清楚。此外，Akt如何参与核因子-βB的激活也不是很清楚。最近，我们在后一个问题上取得了一些进展，证明了CARMA1蛋白是Akt介导的T细胞核因子-βB诱导所必需的。此外，Akt还可以与CARMA1相互作用并调节其定位，此外还可以增加Bcl10的磷酸化，这是在与CARMA1的复合体中发现的。基于我们的初步数据和上述假设，我们提出了三个具体目标。(1)为了更好地了解Akt和CARMA1之间的相互作用如何影响细胞激活，我们将采用各种分子和细胞生物学方法，详细揭示这种相互作用是如何调控的。(2)为了阐明Bcl10磷酸化的作用和调控，我们将定位Bel 10内可诱导的磷酸化位点，并确定Akt在其调节中的作用。(3)为了确定核因子-βB在Akt介导的基因调控和转化中的整体作用，我们将首先利用基因芯片技术和一种强大的核因子-βB途径抑制剂来揭示哪些Akt诱导的基因需要核因子-βB的活性。类似的方法将被用来确定核因子-βB在Akt介导的转化中的作用。这些研究的完成将揭示有关正常和肿瘤细胞生长的两个重要调节因子-Akt和NF-？B之间的合作的重要信息。相关性：许多研究表明Akt的调节失调是细胞转化中的常见事件。Akt在正常和病理细胞功能中的作用由于Akt辐射的多条下游通路的存在而变得复杂。本文描述的研究将有助于更好地理解Akt如何激活其中一条途径--核转录因子-？B家族--以及该途径在Akt介导的基因上调和细胞转化中的作用。这些知识可能最终会导致对Akt调节失调的肿瘤进行更特异和有效的治疗。

DESCRIPTION (provided by applicant): NF-?B family transcription factors are critical regulators of gene transcription. Mutations in the NF-?B pathway are now known to contribute to cellular transformation and the development of cancer. I have been studying the role of the serine/threonine kinase Akt in cellular activation and NF-?B induction. Interestingly, Akt is also a proto-oncogene, and is frequently amplified or activated in cancer. Akt is known to contribute to the activation of numerous downstream pathways, including NF-?B. I hypothesize that activation of NF-?B is important for the effects of Akt on T cell activation and transformation. At this point, the overall role of NF-?B in Akt-mediated transcriptional up-regulation is not clear. Also, it is not known precisely how Akt contributes to NF-?B activation. We have recently made some progress on this latter question, by showing that the protein CARMA1 is required for Akt-mediated NF-?B induction in T cells. Also, Akt can interact with CARMA1 and modulate its localization, in addition to increasing the phosphorylation of Bcl10, which is found in a complex with CARMA1. Based on our preliminary data and the hypothesis stated above, three specific aims are proposed. (1) To better understand how the interaction between Akt and CARMA1 affects cellular activation, we will employ a variety of molecular and cell biological approaches that will reveal in detail how this interaction is regulated. (2) To elucidate the role and regulation of Bcl10 phosphorylation, we will map sites of inducible phosphorylation within Bel 10 and determine the role of Akt in their regulation. (3) To determine the global role of NF-?B in Akt-mediated gene regulation and transformation, we will first use microarray technology and a powerful inhibitor of the NF-?B pathway to reveal which Akt-inducible genes require NF-?B activity. A similar approach will be employed to determine the role of NF-?B in Akt-mediated transformation. Completion of these studies should reveal important information about the cooperation between two important regulators of normal and neoplastic cell growth - Akt and NF-?B. Relevance: Many studies have shown that dysregulation of Akt is a common event in cellular transformation. Understanding the role of Akt in normal and pathological cellular function is complicated by the existence of the multiple downstream pathways that radiate from Akt. The studies described here will lead to a better understanding of how Akt activates one of these pathways - the NF-?B family of transcription factors - and the role of this pathway in Akt-mediated gene upregulation and cellular transformation. Such knowledge may eventually lead to more specific and efficacious treatments for tumors with dysregulated Akt.