Activation of p70 ribosomal protein S6 kinase is an essential step in the DNA damage-dependent signaling pathway responsible for the ultraviolet B-mediated increase in interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3) protein levels in human dermal fibroblasts
P. Brenneisen et al., Activation of p70 ribosomal protein S6 kinase is an essential step in the DNA damage-dependent signaling pathway responsible for the ultraviolet B-mediated increase in interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3) protein levels in human dermal fibroblasts, J BIOL CHEM, 275(6), 2000, pp. 4336-4344
Ultraviolet B (UVB) irradiation has been shown to stimulate the expression
of matrix-degrading metalloproteinases via generation of DNA damage and/or
reactive oxygen species. Matrix-degrading metalloproteinases promote UVB-tr
iggered detrimental long term effects like cancer formation and premature s
kin aging. Here, we were interested in identifying components of the signal
transduction pathway that causally link UVB-mediated DNA damage and induct
ion of matrix-degrading metalloproteinase (MMP)-1/interstitial collagenase
and MMP-3/stromelysin-1 in human dermal fibroblasts in vitro. The activity
of p70 ribosomal S6 kinase, a downstream target of the FK506-binding protei
n- 12/rapamycin-associated protein kinase (FRAP) kinase (RAFT1, mTOR), was
identified to be 4.8 +/- 0.8-fold, and MMP-1 and MMP-3 protein levels 2.4-
and 11.5-fold increased upon UVB irradiation compared with mock-irradiated
controls, The FRAP kinase inhibitor rapamycin and the DNA repair inhibitor
aphidicolin significantly suppressed the UVB-mediated increase in p70 ribos
omal S6 kinase activity by 50-65% and MMP-1 and MMP-3 protein levels by 34-
68% and 42-88% compared with UVB-irradiated fibroblasts, By contrast, the i
nterleukin-1 beta-mediated increase in MMP-1 and MMP-3 protein levels could
not be suppressed by rapamycin, Collectively, our data suggest that the FR
AP-controlled p70 ribosomal S6 kinase is an essential component of a DNA da
mage-dependent, but not of the interleukin-1/cell membrane receptor-depende
nt signaling.