Growth, differentiation, and development of an organism is tightly controlled by the spatial and temporal regulation of transcription factors. NF-kappaB proteins are a large family of transcription factors which control the expression of a vast array of genes involved in immune response, cancer, viral infections, programmed cell death, developmental clues, etc. Unlike most transcription factors, NF-kappaB proteins are sequestered in the cytoplasm in association with inhibitory proteins (IkappaBs). In response to an external signal, the IkappaB proteins are phosphorylated, ubiquitinated, and degraded by proteosomes to allow the release of the NF-kappaB protein to the nucleus where they can bind to the cognate DNA binding sites and activate transcription of specific genes. The seminal event in the activation of NF-kappaB proteins in response to exogenous stimulus is the degradation of IkappaB proteins. In this proposal we are planning to study the components of a large cytoplasmic complex, referred to as IKK, which receives the signal and modulates the degradation of IkappaB protein. We plan to understand the molecular function of the two kinases, IKK1 and IKK2 present in the IKK complex because they phosphorylate IkappaBalpha at unique residues to trigger its degradation process. We have generated mice where the two kinases have been genetically deleted either singly or both of them. The remarkable but quite distinct influences of these kinases on mice development lead us to ask if these kinases have distinctly different roles in growth and development. We plan to study the nature and mechanism of brain malformation in double """"""""knockout"""""""" mice (both IKK1 and IKK2 are removed). We will also study what specific signal pathways each of these kinases respond to in different tissues. By using novel DNA microarray technology (thousands of genes can be analyzed simultaneously) we will identify novel genes induced by NF-kappaB proteins in cell growth and programmed cell death (apoptosis). We also plan to determine if the two kinases are involved in functions other that induced phosphorylation of IkappaB proteins. Finally, we also propose to generate viral vectors containing mutant forms of IKKs or IkappaB proteins and study their effect on experimental model systems like asthma, rheumatoid arthritis, cancer models (radiation damage, chemotoxic agents), and development. We believe that the experiments proposed here will allow us to decipher the molecular mechanism of regulation of NF-kappaB proteins. The detailed knowledge of this important signal pathway will allow us to develop strategies for curing diseases ranging from inflammation to cancer.
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