Cooperation between STAT3 and c-jun suppresses Fas transcription.
Decreased Fas expression during tumor progression often results in a loss of Fas-ligand (FasL)-mediated apoptosis. Human and mouse melanoma exhibit an inverse correlation between the degree of Fas cell surface expression, tumorigenicity, and metastatic capacity. The expression of dominant negative Stat3 or c-Jun in melanoma cells efficiently increased Fas expression and sensitized cells to FasL-induced apoptosis. Stat3+/- as well as c-Jun-/- cells exhibited increased Fas cell surface expression and higher sensitivity to FasL-mediated apoptosis. Suppression of Fas expression by Stat3 and c-Jun is uncoupled from Stat3-mediated transcriptional activation. Our findings indicate that Stat3 oncogenic activities could also be mediated through its cooperation with c-Jun, resulting in downregulation of Fas surface expression, which is implicated in the tumor's ability to resist therapy and metastasize.
Ivanov
V N
VN
The Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
Bhoumik
A
A
Krasilnikov
M
M
Raz
R
R
Owen-Schaub
L B
LB
Levy
D
D
Horvath
C M
CM
Ronai
Z
Z
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053222:Fas Ligand Protein; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000528:radiation effects; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics / Q000528:radiation effects; D020218:Response Elements / Q000235:genetics; D050796:STAT3 Transcription Factor; D017384:Sequence Deletion / Q000235:genetics; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000235:genetics; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D019014:fas Receptor; D004247:DNA