The analysis of mouse models in order to define the roles of IKK/NF-KappaB and JNK signaling in lymphocyte physiology and pathology

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In order to react to environmental changes, cells transmit information from the cell membrane to the nucleus in order to reprogram gene-expression. IκB Kinase (IKK)- mediated activation of NFκB transcription factors and c-Jun N-terminal Kinase (JNK) signaling are two important signaling pathways that relay information during immune responses. They regulate immune cell development and function, cellular proliferation and cell death. NFκB proteins have been implicated in a variety of hereditary and acquired human diseases and constitutive NFκB activation is a hallmark of various B cell malignancies. Likewise, active JNK has been identified in B lymphomas, suggesting a role for aberrant JNK-activity in lymphomagenesis. My proposal aims at elucidating the roles of IKK and JNK signaling in the context of immunity and tumorigenesis through the generation of genetically modified mice. The consequences of absent or constitutively active signaling will be evaluated at the cellular and biochemical level in vivo. In addition, I will employ novel genetic strategies to identify oncogenic events, that co-operate with constitutive IKK or JNK activation to induce tumorigenesis.