The Ras/Raf/MEK/extracellular signal-regulated kinase pathway induces autocrine-paracrine growth inhibition via the leukemia inhibitory factor/JAK/STAT pathway.
Sustained activation of the Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway can lead to cell cycle arrest in many cell types. We have found, with human medullary thyroid cancer (MTC) cells, that activated Ras or c-Raf-1 can induce growth arrest by producing and secreting an autocrine-paracrine factor. This protein was purified from cell culture medium conditioned by Raf-activated MTC cells and was identified by mass spectrometry as leukemia inhibitory factor (LIF). LIF expression upon Raf activation and subsequent activation of JAK-STAT3 was also observed in small cell lung carcinoma cells, suggesting that this autocrine-paracrine signaling may be a common response to Ras/Raf activation. LIF was sufficient to induce growth arrest and differentiation of MTC cells. This effect was mediated through the gp130/JAK/STAT3 pathway, since anti-gp130 blocking antibody or dominant-negative STAT3 blocked the effects of LIF. Thus, LIF expression provides a novel mechanism allowing Ras/Raf signaling to activate the JAK-STAT3 pathway. In addition to this cell-extrinsic growth inhibitory pathway, we find that the Ras/Raf/MEK/ERK pathway induces an intracellular growth inhibitory signal, independent of the LIF/JAK/STAT3 pathway. Therefore, activation of the Ras/Raf/MEK/ERK pathway can lead to growth arrest and differentiation via at least two different signaling pathways. This use of multiple pathways may be important for "fail-safe" induction and maintenance of cell cycle arrest.
Park
Jong-In
JI
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Strock
Christopher J
CJ
Ball
Douglas W
DW
Nelkin
Barry D
BD
D000256:Adenoviridae / Q000235:genetics; D015703:Antigens, CD / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002116:Calcitonin / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D050822:Cytokine Receptor gp130; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D017930:Genes, Reporter; D006131:Growth Inhibitors / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008156:Luciferases / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism*; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D013058:Mass Spectrometry; D008562:Membrane Glycoproteins / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013347:Subcellular Fractions; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism*
D015703:Antigens, CD; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C494199:IL6ST protein, human; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D002116:Calcitonin; D004247:DNA; D008156:Luciferases; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins