Regulation of NF-kB by the Akt kinase

描述（由申请人提供）：NF-？B家族转录因子是基因转录的关键调控因子。NF-?的突变B途径现在已知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在细胞活化和NF-？B感应。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。Akt参与了包括NF- B在内的多种下游通路的激活。我假设NF-？B在Akt对T细胞活化和转化的影响中起重要作用。此时，NF-？B在akt介导的转录上调中尚不清楚。此外，目前还不清楚Akt如何促进NF-？B激活。我们最近在后一个问题上取得了一些进展，表明akt介导的NF-？B诱导T细胞。此外，Akt可以与CARMA1相互作用并调节其定位，除了增加与CARMA1复合物中Bcl10的磷酸化外。根据我们的初步数据和上述假设，提出了三个具体目标。(1)为了更好地理解Akt和CARMA1之间的相互作用如何影响细胞活化，我们将采用多种分子和细胞生物学方法来详细揭示这种相互作用是如何被调节的。(2)为了阐明Bcl10磷酸化的作用和调控，我们将绘制Bcl10诱导磷酸化位点，并确定Akt在其调控中的作用。(3)确定NF-？在akt介导的基因调控和转化中，我们将首先使用微阵列技术和NF-？B途径揭示哪些akt诱导基因需要NF-？B的活动。将采用类似的方法来确定NF-？B在akt介导的转化。这些研究的完成将揭示正常和肿瘤细胞生长的两种重要调节因子- Akt和NF- B之间的合作关系的重要信息。相关性：许多研究表明Akt的失调是细胞转化过程中的一个常见事件。Akt在正常和病理细胞功能中的作用因其辐射的多种下游通路的存在而变得复杂。这里描述的研究将有助于更好地理解Akt如何激活其中一种通路- NF-？B家族转录因子-以及该途径在akt介导的基因上调和细胞转化中的作用。这些知识可能最终导致对Akt失调的肿瘤进行更具体和有效的治疗。

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.