PMID- 11850817
OWN - NLM
STAT- MEDLINE
DCOM- 20020228
LR  - 20220318
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 21
IP  - 7
DP  - 2002 Feb 7
TI  - Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells 
      through p38 MAPK, ATF-2 and cyclin D1.
PG  - 1000-8
AB  - 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.
FAU - Recio, Juan A
AU  - Recio JA
AD  - Laboratory of Molecular Biology, National Cancer Institute, National Institutes 
      of Health, Bethesda, MD 20892-4264, USA.
FAU - Merlino, Glenn
AU  - Merlino G
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Activating Transcription Factor 2)
RN  - 0 (Atf2 protein, mouse)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 136601-57-5 (Cyclin D1)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Activating Transcription Factor 2
MH  - Animals
MH  - Cell Division
MH  - Cell Movement
MH  - Cyclic AMP Response Element-Binding Protein/*physiology
MH  - Cyclin D1/genetics/*physiology
MH  - Hepatocyte Growth Factor/*pharmacology
MH  - Kinetics
MH  - Melanoma/genetics/*metabolism/pathology
MH  - Mice
MH  - Mitogen-Activated Protein Kinases/*physiology
MH  - Phosphatidylinositol 3-Kinases/physiology
MH  - RNA, Messenger/biosynthesis
MH  - Signal Transduction
MH  - Transcription Factors/*physiology
MH  - Transcriptional Activation
MH  - Tumor Cells, Cultured
MH  - Up-Regulation
MH  - p38 Mitogen-Activated Protein Kinases
EDAT- 2002/02/19 10:00
MHDA- 2002/03/01 10:01
CRDT- 2002/02/19 10:00
PHST- 2001/06/01 00:00 [received]
PHST- 2001/10/21 00:00 [revised]
PHST- 2001/10/30 00:00 [accepted]
PHST- 2002/02/19 10:00 [pubmed]
PHST- 2002/03/01 10:01 [medline]
PHST- 2002/02/19 10:00 [entrez]
AID - 10.1038/sj.onc.1205150 [doi]
PST - ppublish
SO  - Oncogene. 2002 Feb 7;21(7):1000-8. doi: 10.1038/sj.onc.1205150.