Oncostatin M induces growth arrest of mammary epithelium via a CCAAT/enhancer-binding protein delta-dependent pathway.
Oncostatin M (OSM), an interleukin 6-type cytokine, induces sustained up-regulation of CCAAT/enhancer-binding protein (C/EBP) delta mRNA and protein in nonneoplastic HC11 mouse mammary epithelial cells. This up-regulation is dependent on signaling by phospho-Stat3 (signal transducers and activators of transcription). The same signaling pathway is activated in two human breast cancer cell lines, a neoplastic mouse mammary epithelial cell line and a second nonneoplastic mouse mammary epithelial cell line. [3H]Thymidine incorporation and flow cytometry demonstrate that OSM inhibits the growth of HC11 cells by reducing the number of S-phase cells. These phenotypic changes are accompanied by reduced expression of S-phase genes with a corresponding increased expression of G0 genes in HC11 cells. Reduction of C/EBPdelta protein in HC11 cells by expression of a C/EBPdelta antisense construct inhibits OSM-mediated growth arrest. These data demonstrate that OSM induces up-regulation of C/EBPdelta via a Stat3-dependent pathway in mammary epithelial cells and that the growth inhibition induced by OSM depends on the presence of C/EBPdelta.
Hutt
Julie A
JA
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA.
DeWille
James W
JW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism*; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D016196:S Phase; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D053683:Oncostatin M; D013936:Thymidine