STAT1 is the founder member of the STAT family of tran scription factors and plays a critical role in interferon regulated gene responses. IFN activates STAT1 through Janus kinase mediated phosphorylation of Tyr701. Activated STAT1 homodimerizes sellekchem and translo cates to the nucleus where it binds to DNA and initiates transcription of IFN regulated genes. The X ray structure of the DNA bound STAT1 dimer shows a contiguous C shaped clamp around DNA, that is mediated by specific interactions between the SH2 domain and the tyrosine phosphorylated C terminal tail segment of the monomers. Small ubiquitin like modifier proteins belong to the family of ubiquitin like protein modifiers, collect ively termed Ubls, that are covalently attached to sub strate proteins by a cascade of enzymatic reactions.

The conjugation Inhibitors,Modulators,Libraries is regulated by distinct SUMO specific enzymes such as E1 activating enzyme Aos1 Uba2 and the E2 conjugase Ubc9. The protein inhibitor of acti vated STAT family of proteins, PIAS1, PIAS3, PIASx and PIASy have been shown to function as E3 type ligases to promote SUMO conjugation to the target proteins. PIAS1 functions as a negative regulator of STAT1 mediated transcription through interaction with the dimerized STAT1 and by inhibiting STAT1 DNA binding. Interestingly, PIAS proteins have also been shown to promote sumoylation of STAT1 at single Lys703 amino acid residue within the SUMO consensus sequence 702IKTE705 in the C terminal region of STAT1. Furthermore, it has been Inhibitors,Modulators,Libraries shown that mitogen activated protein kinase induced phosphorylation of Ser727 GSK-3 in Inhibitors,Modulators,Libraries STAT1 promotes interaction of STAT1 with PIAS1 and leads to enhanced STAT1 sumoylation.

Several studies suggest that sumoylation has a negative effect on STAT1 mediated gene responses. Sumoylation site Lys703 is in a close proximity to Tyr701 that is required for STAT1 activation, and sumoylation Inhibitors,Modulators,Libraries has been shown to directly inhibit STAT1 Tyr701 phosphorylation. Sumoylation has also been shown to prevent condensation of STAT1 oligo mers in the nuclear paracrystals, and thereby increase the solubility of STAT1 and promote its dephosphoryla tion. Recently, it was discovered that in addition to human STAT1, also murine STAT5 and Drosophila Stat92E are regulated through SUMO conjugation, confirming that sumoylation has an evolutionary con served role in regulation of the cytokine signaling.

This study was aimed to investigate the mechanism by which sumoylation regulates STAT1 activity. Inspection of molecular model indicates that SUMO consensus site is well exposed in STAT1 dimer, and it is accessible selleck chemicals llc for propitious interactions with regulatory proteins. The constructed molecular model of SUMO 1 conjugated STAT1 dimer further suggested that SUMO 1 moiety is oriented towards DNA, thus able to affect the DNA binding properties of STAT1 with its presence.