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 const...

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Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 279; no. 37; pp. 38787 - 38796
Main Authors:	Schick, Nicole, Oakeley, Edward J., Hynes, Nancy E., Badache, Ali
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 10-09-2004 American Society for Biochemistry and Molecular Biology
Subjects:	Blotting, Western Cell Cycle Cell Division Cell Line Cell Line, Tumor DNA - chemistry DNA-Binding Proteins - metabolism DNA-Binding Proteins - physiology ETS Translocation Variant 6 Protein Flow Cytometry G1 Phase G2 Phase Gene Deletion Humans Lac Operon Luciferases - metabolism Mutation Oligonucleotide Array Sequence Analysis Oligonucleotides - chemistry Plasmids - metabolism Precipitin Tests Protein Structure, Tertiary Proto-Oncogene Proteins c-ets Receptors, Estrogen - metabolism Recombinant Proteins - chemistry Repressor Proteins - metabolism Repressor Proteins - physiology Reverse Transcriptase Polymerase Chain Reaction RNA, Small Interfering - metabolism Signal Transduction STAT3 Transcription Factor Time Factors Trans-Activators - metabolism Transcription, Genetic Transfection
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M312581200