Regulation of NF-kB by the Akt kinase

NF-？B家族转录因子是转录调控的关键因子， 基因转录NF-？B途径现在已知有助于细胞凋亡。 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-κ B中作用B诱导。有趣的是，Akt也是一种原癌基因， 在癌症中经常被放大或激活。已知Akt有助于激活许多 下游途径，包括NF-？B。我推测NF-？B对于 Akt对T细胞活化和转化的影响。在这一点上，NF-？Akt介导的B 转录上调尚不清楚。此外，目前还不清楚Akt是如何促进 NF-？B激活。我们最近在后一个问题上取得了一些进展，表明 蛋白CARMA 1是必需的Akt介导的NF-？T细胞中的B诱导。此外，Akt可以与 CARMA 1和调节其定位，除了增加Bcl 10的磷酸化，这是 在与CARMA 1的复合物中发现。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 CARMA 1影响细胞激活，我们将采用多种分子和细胞生物学方法 这将详细揭示这种相互作用是如何调节的。(2)阐明的作用和调节 Bcl 10磷酸化，我们将绘制Bcl 10内诱导磷酸化的位点，并确定Bcl 10的磷酸化水平。 Akt在其调节中的作用。(3)确定NF-？B与Akt介导的基因调控 和转化，我们将首先使用微阵列技术和NF-？B 途径，以揭示哪些Akt诱导基因需要NF-？B活性。类似的方法将是 用于确定NF-？B在Akt介导的转化中。完成这些研究 应该揭示两个重要的正常监管机构之间的合作的重要信息 和肿瘤细胞生长- Akt和NF-？B。相关性：许多研究表明， Akt是细胞转化中的常见事件。了解Akt在正常和 病理性细胞功能由于存在多种下游途径而变得复杂， 从Akt辐射。这里描述的研究将导致更好地理解Akt如何激活 其中一个途径NF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。这些知识最终可能会导致更多 用于具有失调Akt的肿瘤的特异性和有效的治疗。

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.