The Ras/Raf/MEK/extracellular signal-regulated kinase pathway induces autocrine-paracrine growth inhibition via the leukemia inhibitory factor/JAK/STAT pathway. Mol Cell Biol 2003 Jan;23(2):543-54
Date
01/02/2003Pubmed ID
12509453Pubmed Central ID
PMC151536DOI
10.1128/MCB.23.2.543-554.2003Scopus ID
2-s2.0-0037221065 (requires institutional sign-in at Scopus site) 112 CitationsAbstract
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.
Author List
Park JI, Strock CJ, Ball DW, Nelkin BDAuthor
Jong-In Park PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenoviridaeAntigens, CD
Blotting, Northern
Blotting, Western
Calcitonin
Cell Cycle
Cell Differentiation
Cell Division
Cell Line
Culture Media, Conditioned
Cytokine Receptor gp130
DNA
DNA-Binding Proteins
Enzyme Activation
Genes, Reporter
Growth Inhibitors
Humans
Immunoblotting
Interleukin-6
Leukemia Inhibitory Factor
Luciferases
Lymphokines
MAP Kinase Kinase 1
MAP Kinase Kinase 2
Mass Spectrometry
Membrane Glycoproteins
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
Models, Biological
Plasmids
Protein Binding
Protein-Tyrosine Kinases
Proto-Oncogene Proteins c-raf
Reverse Transcriptase Polymerase Chain Reaction
STAT3 Transcription Factor
Signal Transduction
Subcellular Fractions
Time Factors
Trans-Activators
Tumor Cells, Cultured
ras Proteins
