Regulation of NF-kB by the Akt kinase

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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 Aktmediated 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 Aktmediated gene upregulation and cellular transformation. Such knowledge may eventually lead to more specific and efficacious treatments for tumors with dysregulated Akt.