Ultraviolet A induced modulation of gap junctional intercellular communication by P38 MAPK activation in human keratinocytes.
Aberrant gap junctional intercellular communication (GJIC) has been implicated in tumor development and progression. UltravioletA (UVA)-induced oxidative stress has been associated with skin carcinogenesis. We report a potential link between GJIC and the cellular stress response induced by UVA in normal human keratinocytes (NHK). In this study, UVA irradiation (10 J/cm(2)) compromised GJIC integrity in absence of cytotoxic effects as demonstrated by the absence of cell death and by the reversibility of GJIC down-regulation. Inhibition of communication by UVA was associated with hyperphosphorylation and decreased expression of connexin43 (Cx43), the most abundant gap junction protein expressed by keratinocytes. Cx43 hyperphosphorylation induced by UVA is, at least in part, mediated through mitogen-activated protein kinase (MAPK) activation as Ser279 and Ser282 sites, two downstream direct targets of p38 MAPK were found to be phosphorylated after UVA treatment. However, inhibition of p38 MAPK activity did not significantly protect from cell-cell communication inhibition because of a strong cellular cytotoxicity observed with SB202190 and SB203580, two selective inhibitors of p38 MAPK, in combination with UVA that compromises the outcome of dye transfer assay. By contrast, in Hacat cell line, inhibition of p38 activity reduced both phosphorylation and degradation of Cx43, demonstrating that these events are correlated.
Bellei
Barbara
B
San Gallicano Dermatological Institute IRCCS, Rome, Italy. citolab@ifo.it
Mastrofrancesco
Arianna
A
Briganti
Stefania
S
Aspite
Nicaela
N
Ale-Agha
Niloofar
N
Sies
Helmut
H
Picardo
Mauro
M
D002450:Cell Communication / Q000502:physiology / Q000528:radiation effects*; D002462:Cell Membrane / Q000528:radiation effects; D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000528:radiation effects; D017629:Gap Junctions / Q000502:physiology / Q000528:radiation effects*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000528:radiation effects; D010766:Phosphorylation / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D018031:Connexin 43; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases