STRA13 interacts with STAT3 and modulates transcription of STAT3-dependent targets.
STRA13 is a pVHL-dependent bHLH transcription factor up-regulated on the mRNA level in multiple cancer cell lines and implicated recently in the regulation of immune cell homeostasis and autoimmunity. In searching for STRA13-interacting proteins with oncogenic potential by the yeast two-hybrid screening, we identified STAT3 beta as a STRA13-binding partner. We showed that STRA13 binds predominantly to phosphorylated (active) STAT3 alpha and beta isoforms via its HLH and C-terminal regions. We also found that STRA13 was able to activate transcription from STAT-dependent cis-elements. Expression of endogenous STRA13 was shown to be cytokine-inducible, consistent with STRA13 involvement in STAT-dependent transcription regulation. We demonstrated that the STAT3-regulated promoter of the pro-apoptotic Fas gene was activated upon STRA13 over-expression and that co-expression of STRA13 with STAT3 beta or STAT3 alpha modulated the transcriptional outcome. Forced expression of STRA13 induced apoptosis, in agreement with the STRA13 activation effect on the Fas promoter. Simultaneous expression of STRA13 and STAT3 beta resulted in alleviation of the STRA13 pro-apoptotic effect. Thus, for the first time, we identify STRA13 as a STAT3 partner and provide a consistent line of evidence for STRA13 involvement into regulation of apoptosis via the STAT pathways.
Ivanova
A V
AV
Basic Research Program, SAIC-Frederick Inc., National Cancer Institute at Frederick, National Institutes of HEalth, Frederick, MD 21702, USA. ivanova@mail.ncifcrf.gov
Ivanov
S V
SV
Zhang
X
X
Ivanov
V N
VN
Timofeeva
O A
OA
Lerman
M I
MI
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011233:Precipitin Tests; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D019014:fas Receptor / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D008156:Luciferases; D020033:Protein Isoforms; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D019014:fas Receptor; C107989:BHLHE40 protein, human; C491539:Bhlhe40 protein, mouse; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse