Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1

Oncogene. 2002 Feb 7;21(7):1000-8. doi: 10.1038/sj.onc.1205150.

Abstract

Members of the mitogen-activated protein kinase (MAPK) superfamily, including p38 kinase and SAPK/JNK, play a central role in mediating cellular response to environmental stress, growth factors and cytokines. Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional cytokine capable of eliciting mitogenic, motogenic and morphogenetic activities in responsive cells, and has been implicated in tumor development and metastasis. Binding of HGF/SF to its tyrosine kinase receptor c-Met stimulates multiple signal transduction pathways, leading to the activation of numerous transcription factors. We here report that HGF/SF can induce cyclin D1 expression in mouse melanoma cells, and that this up-regulation is mediated in part by the activating transcription factor-2 (ATF-2). HGF/SF-mediated phosphorylation of ATF-2 was reduced in the presence of either the p38 kinase-specific inhibitor SB203580, a dominant negative p38 mutant, the SAPK/JNK inhibitor JNK-interacting protein-1 (JIP-1), or the phosphatidylinositol 3-kinase (PI3K)-specific inhibitor LY294002. Activation of p38 kinase by HGF/SF was partially blocked by the PI3K-specific inhibitor as well. The upstream kinases for p38, MKK3/6, did not become activated following HGF/SF exposure, and ATF-2 activation was undiminished by transient transfection of a dominant negative MKK6 mutant. However, transcriptional up-regulation of cyclin D1 by HGF/SF was partially inhibited by the p38 kinase-specific inhibitor, and cyclin D1 protein induction was partially blocked by a dominant negative ATF-2 mutant. Notably, the p38 kinase-specific inhibitor was able to block melanoma cell proliferation but not motility. We conclude that the ATF-2 transcription factor becomes activated by HGF/SF through p38 MAPK and SAPK/JNK. Moreover, the p38-ATF-2 pathway can help mediate proliferation signals in tumor cells through transcriptional activation of key cell cycle regulators.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activating Transcription Factor 2
  • Animals
  • Cell Division
  • Cell Movement
  • Cyclic AMP Response Element-Binding Protein / physiology*
  • Cyclin D1 / genetics
  • Cyclin D1 / physiology*
  • Hepatocyte Growth Factor / pharmacology*
  • Kinetics
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Mice
  • Mitogen-Activated Protein Kinases / physiology*
  • Phosphatidylinositol 3-Kinases / physiology
  • RNA, Messenger / biosynthesis
  • Signal Transduction
  • Transcription Factors / physiology*
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Activating Transcription Factor 2
  • Atf2 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • RNA, Messenger
  • Transcription Factors
  • Cyclin D1
  • Hepatocyte Growth Factor
  • Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases