Identifying a common molecular mechanism for inhibition of MITF and STAT3 by PIAS3

Levy C, Lee YN, Nechushtan H, Schueler-Furman O, Sonnenblick A, Hacohen S and Razin E
Source: Blood
Publication Date: (2006)
Issue: 107(7): 2839-45
Research Area:
Cancer Research/Cell Biology
Immunotherapy / Hematology
Cells used in publication:
Species: rat
Tissue Origin: blood
Nucleofector® I/II/2b
Protein inhibitor of activated STAT3 (PIAS3) functions in vivo as a key molecule in suppressing the transcriptional activity of both microphthalmia transcription factor (MITF) and signal transducer and activator of transcription 3 (STAT3), two transcription factors that play a major role in the regulation of growth and function in mast cells and melanocytes. Previously we have demonstrated binding of PIAS3 to MITF leading to the inhibition of MITF transcriptional activity. Following cellular activation, PIAS3 is released from MITF and binds to STAT3. Now we have localized a common binding motif in PIAS3 for MITF and STAT3. This motif (PIAS82-132), which contains 50 amino acids, is sufficient for the inhibition of both MITF and STAT3. Three-dimensional protein modeling demonstrated that this motif contains two alpha helices. Disruption of one of the helices led to the loss of PIAS3 inhibitory activity. In addition to contributing to our understanding of the mechanisms of PIAS3 activity, these results could pave the way towards the formulation of an anti-oncogenic agent for the inhibition of both STAT3 and MITF.