Abstract
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-triggered detrimental long term effects like cancer formation and premature skin aging. Here, we were interested in identifying components of the signal transduction pathway that causally link UVB-mediated DNA damage and induction 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 protein-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 ribosomal 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 interleukin-1beta-mediated increase in MMP-1 and MMP-3 protein levels could not be suppressed by rapamycin. Collectively, our data suggest that the FRAP-controlled p70 ribosomal S6 kinase is an essential component of a DNA damage-dependent, but not of the interleukin-1/cell membrane receptor-dependent signaling.
Highlights
In past years, two signaling pathways for the mammalian ultraviolet (UV) response have been identified
In this study we have focused on the identification of components of the DNA damage-dependent signal transduction pathway being causally involved in the induction of two major members of the matrixdegrading metalloproteinase (MMP) family following UVB irradiation
We were able to show that the activity of p70 ribosomal S6 kinase (p70S6k), but not p70 S6 Ribosomal Kinase (p70S6k) protein synthesis, is UVB-dependently stimulated and that p70S6k is essentially required for the UVB/DNA damage-initiated signal cascade(s) leading to the induction of MMP-1 and MMP-3
Summary
Two signaling pathways for the mammalian ultraviolet (UV) response have been identified. UVB-mediated Increase in Interstitial Collagenase (MMP-1) and Stromelysin-1 (MMP-3) Protein Levels Can Partly Be Suppressed by Rapamycin and Aphidicolin—In order to study which components of the UVB-dependent and DNA damageinitiated signaling pathway are causally involved in the induction of matrix-degrading metalloproteinases, we here used the DNA repair inhibitor aphidicolin [41] and rapamycin, an immunosuppressant which (via the FKBP) binds and inhibits the FRAP kinase [32, 40], a recently identified DNA protein kinase [36, 38].
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have