Interferons (IFNs) play a critical role in viral host defenses. Although biochemical studies have elucidated two functionally and structurally distinct classes of IFNs (type I and type II), it has been the genetic studies, with receptor deficient mice, that have defined the distinct but complimentary roles these two classes of interferons play. With the recent characterization of the JAK-STAT signaling paradigm, and the critical role it plays in IFN signal transduction, it is now possible to study how the two classes of IFNs mediate their distinct effects within the cell. JAKs crucial receptor associated tyrosine kinases. STATs (Signal Transducers and Activators of Transcription) are cytoplasmic proteins, which upon tyrosine phosphorylation, dimerize into active Signal Transducing Factors (STFs). These STFs than translocate to the nucleus where they bind specific sequences in the promoters of target genes, culminating in the induction of transcription. Consistent with their biology, type I and type II IFNs have been shown to signal through distinct, but partially overlapping JAK-STAT signaling pathways. The pathway activated by type II IFN (i.e., IFN-gamma) is simpler, consisting of a Stat1 homodimer (i.e., STF-IFNgamma) which binds an enhancer known as the Gamma Activation Site (GAS). The STF activated by type I IFNs (e.g., IFN-alpha), STF-IFN-alpha, consists of a Stat1:Stat2 heterodimer and a 48 kDa DNA binding protein. It binds an enhancer known as the IFN Stimulated Response Element (ISRE). Stat2 is the only STAT which is unable to bind the GAS elements either as a homodimer or heterodimer with another STAT. Recent studies from our laboratory have elucidated several additional notable Stat2 features. We have been able to demonstrate that Stat2 forms a stable homodimer that binds to DNA elements that is distinct from the GAS or ISRE sites, strongly implicating it in a second signaling pathway. We have also isolated the murine homolog of Stat2 and determine that its carboxy terminus is uncharacteristically distinct from the human Stat2. Yet, biological responses and signals stimulated by type I IFNs are conserved between these species. We plan to explore the unique features of Stat2 in mediating both known (e.g., IFN and anti viral) and unknown signals through both genetic and biochemical approaches. Specifically we propose to: 1. Create a Stat2 knock out mouse. 2. Carry out a functional comparison of the murine and human Stat2 homologs. 3. Identify the DNA binding elements for Stat2 homodimers.
| Wang, Jianping; Pham-Mitchell, Ngan; Schindler, Christian et al. (2003) Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-alpha-stimulated STAT2-independent production of IFN-gamma in the brain. J Clin Invest 112:535-43 |
| Bhattacharya, Samita; Schindler, Christian (2003) Regulation of Stat3 nuclear export. J Clin Invest 111:553-9 |
| Park, C; Li, S; Cha, E et al. (2000) Immune response in Stat2 knockout mice. Immunity 13:795-804 |
