Identifying a common molecular mechanism for inhibition of MITF and STAT3 by PIAS3.
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), 2 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 2 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 toward the formulation of an antioncogenic agent for the inhibition of both STAT3 and MITF.
Levy
Carmit
C
Department of Biochemistry, Hebrew University Hadassah Medical School, POB 12272, Jerusalem 91120, Israel.
Lee
Yu-Nee
YN
Nechushtan
Hovav
H
Schueler-Furman
Ora
O
Sonnenblick
Amir
A
Hacohen
Shelley
S
Razin
Ehud
E
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D017124:Conserved Sequence; D017931:DNA Primers; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D008969:Molecular Sequence Data; D010957:Plasmids; D020641:Polymorphism, Single Nucleotide; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000502:physiology*; D051381:Rats; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D017931:DNA Primers; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; C109279:Pias3 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse