Activation of Stat3 by cell confluence reveals negative regulation of Stat3 by cdk2.
The signal transducing protein Stat3 activates gene transcription in cells in response to multiple cytokines. Constitutive activation of Stat3 has been observed in solid tumors including head and neck squamous cell carcinoma. Stat3 activation in cancer has been associated with autocrine stimulatory loops and is believed to convey a growth advantage to cells. We now demonstrate ligand-independent activation of Stat3 by high cell density in multiple cancer cell lines. Activation of Stat3 is associated with antiproliferative rather than proliferative conditions. Interference with cdk2 activity upregulates Stat3 phosphorylation and Stat3-directed DNA-binding activity. Our data supports a model in which Stat3 activity is partially suppressed by cdk2 in growing cells and derepressed upon cell confluence.
Steinman
Richard A
RA
Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. steinman@pitt.edu
Wentzel
Abbey
A
Lu
Yalin
Y
Stehle
Christine
C
Grandis
Jennifer Rubin
JR
D016475:3T3 Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D042846:CDC2-CDC28 Kinases; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects; D002455:Cell Division / Q000502:physiology; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011687:Purines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; D000077546:Roscovitine; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D020830:rac1 GTP-Binding Protein