TEL/ETV6 is a signal transducer and activator of transcription 3 (Stat3)-induced repressor of Stat3 activity.
The signal transducer and activator of transcription 3 (Stat3) transcription factor is required for the antiproliferative effects induced by cytokines, such as the interleukin-6 type. In order to investigate the role of Stat3 in inhibition of cell proliferation, we have used an inducible Stat3 construct in A375 melanoma cells. We found that activation of Stat3 to moderate levels was sufficient to repress A375 proliferation, by slowing cell transit through the cell cycle. Enhanced and prolonged Stat3 activity led to cell cycle arrest and apoptosis. Genes whose expression was altered by Stat3 activation were identified by oligonucleotide microarray analysis. We found that TEL (ETV6), a novel Stat3 target identified in this study, is a negative regulator of Stat3 activity. Small interfering RNA-mediated inhibition of TEL expression resulted in increased Stat3-dependent transcriptional activity and stronger Stat3 antiproliferative activity. Confirming these results, overexpression of TEL repressed Stat3 transcriptional activity. Intriguingly, Stat3 repression did not require TEL DNA binding and appeared to proceed via recruitment of TEL to Stat3. Inhibition of Stat3 activity by TEL represents a novel mechanism regulating the Stat3 signaling pathway.
Schick
Nicole
N
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel CH-4058, Switzerland.
Oakeley
Edward J
EJ
Hynes
Nancy E
NE
Badache
Ali
A
D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology*; D005434:Flow Cytometry; D016193:G1 Phase; D016195:G2 Phase; D017353:Gene Deletion; D006801:Humans; D007763:Lac Operon; D008156:Luciferases / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D050783:Proto-Oncogene Proteins c-ets; D034741:RNA, Small Interfering / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D000097764:ETS Translocation Variant 6 Protein
D004247:DNA; D004268:DNA-Binding Proteins; D008156:Luciferases; D009841:Oligonucleotides; D050783:Proto-Oncogene Proteins c-ets; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000097764:ETS Translocation Variant 6 Protein; C494086:STAT3 protein, human