Cytokines regulate hematopoietic cell growth and differentiation by inducing the expression of specific target genes. We have recently isolated a cytokine-inducible immediate-early gene, DUB-1, that encodes a deubiquitinating enzyme with growth regulatory activity. Interestingly, DUB-I is a member of a novel subfamily of deubiquitinating enzymes (called DUB proteins) that are induced by different cytokines and that mediate specific cytokine signals. During the proposed five year study period, we plan to study the cellular function of the DUB enzymes and the mechanism of cytokine specific induction.
In Specific Aim #1, we will utilize in vitro mutagenesis of the DUB-I cDNA in order to identify critical DUB-I domains required for deubiquitinating activity and growth regulatory activity. Mutant DUB-1 polypeptides will be used to identify binding proteins and potential substrate proteins.
In Specific Aim #2, we will identify critical sequence determinants of DUB-I protein stability.
In Specific Aim #3, we will generated DUB- deficient and DUB transgenic mice in order to assess the in vivo function of this protein subfamily. Finally, in Specific Aim #4, we will compare the enhancers of the DUB-I and DUB-2 gene for DNA sequences and binding proteins that determine the basis of cytokine-specific gene induction.
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