PMID- 11821397
OWN - NLM
STAT- MEDLINE
DCOM- 20020607
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 277
IP  - 16
DP  - 2002 Apr 19
TI  - Hepatocyte growth factor/scatter factor inhibits UVB-induced apoptosis of human 
      keratinocytes but not of keratinocyte-derived cell lines via the 
      phosphatidylinositol 3-kinase/AKT pathway.
PG  - 14146-52
AB  - Acute irreparable UV-induced DNA damage leads to apoptosis of epidermal 
      keratinocytes (KC) and the formation of sunburn cells, whereas less severely 
      damaged cells survive but harbor the potential of tumor formation. Here we report 
      that hepatocyte growth factor/scatter factor (HGF/SF) prevents UVB-induced 
      apoptosis in primary KC cultured in vitro. When we analyzed the signaling 
      pathways initiated by the HGF/SF receptor c-met, we found that the 
      phosphatidylinositol (PI) 3-kinase and its downstream-element AKT and the 
      mitogen-activated protein (MAP) kinase were activated. Inhibition of PI 3-kinase 
      led to a complete abrogation of the anti-apoptotic effect of HGF/SF, whereas 
      blockade of the MAP kinase pathway had no effect. In contrast to the observation 
      with primary KC, HGF/SF could not enhance survival after UVB irradiation of HaCaT 
      and A431 cell lines, despite the fact that in these cells the PI 3-kinase and MAP 
      kinase pathways were also activated by HGF/SF. Cell cycle analysis of KC revealed 
      a G(2)/M arrest after UVB irradiation and a complete loss of proliferating cells. 
      Because HGF/SF in the skin is produced by dermal fibroblasts, our findings 
      suggest that the HGF/SF-mediated rescue of KC from apoptosis represents an 
      important paracrine loop by which UVB-damaged KC can be kept alive to maintain 
      the epidermal barrier function but cannot further proliferate, thereby preventing 
      the induction of epithelial skin tumors.
FAU - Mildner, Michael
AU  - Mildner M
AD  - Division of Immunology, Allergy and Infectious Diseases, Department of 
      Dermatology, Vienna Medical School, Wahringer Gurtel 18-20, A-1090 Vienna, 
      Austria.
FAU - Eckhart, Leopold
AU  - Eckhart L
FAU - Lengauer, Barbara
AU  - Lengauer B
FAU - Tschachler, Erwin
AU  - Tschachler E
LA  - eng
PT  - Journal Article
DEP - 20020130
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Enzyme Inhibitors)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - *Apoptosis
MH  - Blotting, Western
MH  - Caspase 3
MH  - Caspases/metabolism
MH  - Cell Cycle
MH  - Cell Division
MH  - Cell Line
MH  - Cell Line, Transformed
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Hepatocyte Growth Factor/*metabolism
MH  - Humans
MH  - Keratinocytes/cytology/*metabolism
MH  - MAP Kinase Signaling System
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation
MH  - Skin Neoplasms/prevention & control
MH  - Time Factors
MH  - Tumor Cells, Cultured
MH  - *Ultraviolet Rays
EDAT- 2002/02/01 10:00
MHDA- 2002/06/12 10:01
CRDT- 2002/02/01 10:00
PHST- 2002/02/01 10:00 [pubmed]
PHST- 2002/06/12 10:01 [medline]
PHST- 2002/02/01 10:00 [entrez]
AID - S0021-9258(19)61020-3 [pii]
AID - 10.1074/jbc.M110687200 [doi]
PST - ppublish
SO  - J Biol Chem. 2002 Apr 19;277(16):14146-52. doi: 10.1074/jbc.M110687200. Epub 2002 
      Jan 30.