Identification of the interleukin-6/oncostatin M response element in the rat tissue inhibitor of metalloproteinases-1 (TIMP-1) promoter.
The rat tissue inhibitor of metalloproteinase 1 (TIMP-1) gene is expressed in rat hepatocytes, and this expression is up-regulated by interleukin 6 (IL-6). We report here the cloning of the 5' flanking region of the rat TIMP-1 gene and identification of an IL-6/oncostatin M (OSM) response element at -64 to -36 which functions in hepatic cells. Within this element we have identified two functional binding sites for transcription factors AP-1 (activatory protein-1) and STAT (signal transducer and activator of transcription). IL-6/OSM stimulation induces binding of a protein, identified as STAT3, to the IL-6/OSM response element, while binding of the AP-1 protein was constitutive. Binding sites for both AP-1 and STAT3 are necessary for full responsiveness of the TIMP-1 promoter to IL-6/OSM, as shown by deletion and mutation analysis. Furthermore, the entire IL-6/OSM response element conferred responsiveness onto a heterologous promoter, whereas this has not been observed when AP-1 and STAT elements were separately tested.
Bugno
M
M
Institute of Molecular Biology, Jagiellonian University, Krakow, Poland.
Graeve
L
L
Gatsios
P
P
Koj
A
A
Heinrich
P C
PC
Travis
J
J
Kordula
T
T
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D006528:Carcinoma, Hepatocellular; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D017353:Gene Deletion; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008969:Molecular Sequence Data; D053683:Oncostatin M; D010455:Peptides / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D050796:STAT3 Transcription Factor; D019714:Tissue Inhibitor of Metalloproteinases; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D006023:Glycoproteins; D015850:Interleukin-6; C508351:OSM protein, human; D010455:Peptides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; D019714:Tissue Inhibitor of Metalloproteinases; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D053683:Oncostatin M