PMID- 10645003
OWN - NLM
STAT- MEDLINE
DCOM- 20000217
LR  - 20121115
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 19
IP  - 2
DP  - 2000 Jan 13
TI  - Inhibition of collagenase-3 (MMP-13) expression in transformed human
      keratinocytes by interferon-gamma is associated with activation of extracellular 
      signal-regulated kinase-1,2 and STAT1.
PG  - 248-57
AB  - Collagenase-3 (MMP-13) is characterized by an exceptionally wide substrate
      specificity and restricted expression. MMP-13 is specifically expressed by
      transformed human keratinocytes in squamous cell carcinomas in vivo and its
      expression correlates with their invasion capacity. Here, we show, that
      interferon-gamma (IFN-gamma) markedly inhibits expression of MMP-13 by human
      cutaneous SCC cells (UT-SCC-7) and by ras-transformed human epidermal
      keratinocytes (A-5 cells) at the transcriptional level. In addition, IFN-gamma
      inhibits collagenase-1 (MMP-1) expression in these cells. IFN-gamma abolished the
      enhancement of MMP-13 and MMP-1 expression by transforming growth factor-beta
      (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha), and inhibited invasion of
      A-5 cells through type I collagen. IFN-gamma also rapidly and transiently
      activates extracellular signal-regulated kinase 1,2 (ERK1,2) and blocking ERK1,2 
      pathway (Raf/MEK1,2/ERK1,2) by specific MEK1,2 inhibitor PD98059 partially (by
      50%) prevents Ser-727 phosphorylation of STAT1 and suppression of MMP-13
      expression by IFN-gamma. Furthermore, Ser-727 phosphorylation of STAT1 by ERK1,2,
      or independently of ERK1,2 activation is associated with marked reduction in
      MMP-13 expression. These observations identify a novel role for IFN-gamma as a
      potent inhibitor of collagenolytic activity and invasion of transformed squamous 
      epithelial cells, and show that inhibition of MMP-13 expression by IFN-gamma
      involves activation of ERK1,2 and STAT1.
FAU - Ala-aho, R
AU  - Ala-aho R
AD  - MediCity Research Laboratory, Department of Medical Biochemistry, University of
      Turku, FIN-20520 Turku, Finland.
FAU - Johansson, N
AU  - Johansson N
FAU - Grenman, R
AU  - Grenman R
FAU - Fusenig, N E
AU  - Fusenig NE
FAU - Lopez-Otin, C
AU  - Lopez-Otin C
FAU - Kahari, V M
AU  - Kahari VM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Matrix Metalloproteinase Inhibitors)
RN  - 0 (Recombinant Proteins)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (STAT1 protein, human)
RN  - 0 (Trans-Activators)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.4.24.- (Collagenases)
RN  - EC 3.4.24.- (MMP13 protein, human)
RN  - EC 3.4.24.- (Matrix Metalloproteinase 13)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Cell Line, Transformed
MH  - Cell Survival/drug effects
MH  - Cell Transformation, Neoplastic/*drug effects/*metabolism
MH  - Collagenases/*biosynthesis/genetics
MH  - DNA-Binding Proteins/*metabolism
MH  - Enzyme Activation/drug effects
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - Interferon-gamma/*pharmacology
MH  - Keratinocytes/drug effects/*enzymology/metabolism
MH  - Matrix Metalloproteinase 13
MH  - *Matrix Metalloproteinase Inhibitors
MH  - Matrix Metalloproteinases/*biosynthesis/genetics
MH  - Mitogen-Activated Protein Kinase 1/*metabolism
MH  - Mitogen-Activated Protein Kinase 3
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Organ Specificity/genetics
MH  - Recombinant Proteins
MH  - STAT1 Transcription Factor
MH  - Trans-Activators/*metabolism
MH  - Transcription, Genetic/drug effects/genetics
MH  - Transforming Growth Factor beta/antagonists & inhibitors
MH  - Tumor Cells, Cultured
MH  - Tumor Necrosis Factor-alpha/antagonists & inhibitors
EDAT- 2000/01/25 09:00
MHDA- 2000/02/19 09:00
CRDT- 2000/01/25 09:00
PHST- 2000/01/25 09:00 [pubmed]
PHST- 2000/02/19 09:00 [medline]
PHST- 2000/01/25 09:00 [entrez]
AID - 10.1038/sj.onc.1203306 [doi]
PST - ppublish
SO  - Oncogene. 2000 Jan 13;19(2):248-57. doi: 10.1038/sj.onc.1203306.