Interleukin (It)-5 is a member of a small family of cytokines (IL-3, IL-5, & GM-CSF) that play an important role in myeloid development. IL-5 however exhibits specificity for eosinophils, accounting for its unique role in promoting the eosinophilia that is seen in a number of human diseases, including asthma. IL-5, IL-3 and GM-CSF transduce signals through two members of the STAT (Signal Transducer and Activator of Transcription) family, Stat5a and Stat5b. Like other STATs, Stat5a and Sta5b transduce ligand specific signals from the receptor to the nucleus, where they promote the transcription of a specific set of genes. STATs share a number of structural motifs that are likely to contribute to their signaling fidelity. This includes an amino terminal four-bundle-helix domain of unknown function, a DNA binding domain, an SH2 domain and carboxy terminal transcriptional activation domain. Our preliminary studies indicate that the four-bundle-helix domain both regulates DNA binding activity and mediates association with a newly identified regulatory protein, StIP1 (Stat Interacting Protein). Stat5 is one of the more pleitrophic members of the STAT family and has been implicated in determining multiple cell fates in both myelocytes and lymphocytes. These studies suggest that the duration of Stat5 signaling is important in determining biological response. Whereas StIP1 and the four-bundle-helix domain appear to contribute to Stat5 activation, signal decay is also known to be tightly regulated. Consistent with this, constitutive activation of Stat5 has been shown to promote myeloid dysregulation. We plan to study how the four-bundle-helix and StIP1 regulate STAT activity and determine the significance of signal decay on the biological response transduced by Stat5. Specifically we propose to: 1. Further characterize StIP1. 2. Functionally characterize the STAT four-bundle-helix. 3. Explore the role of Stat5 signal decay in primary leukocytes.
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