Repeated exposures to UVB induce differentiation rather than senescence of human keratinocytes lacking p16(INK-4A).
Skin cancers and extrinsic aging are delayed consequences of cumulative UV radiation insults. Exposure of human keratinocytes to UVB has been previously shown to trigger premature senescence. In order to explore the involvement of the cyclin-dependent kinase inhibitor p16(INK-4a) in UVB-induced premature senescence, we developed an original model of repeated sublethal exposures of human keratinocytes deficient in p16(INK-4a). We did not observe any significant increase of senescence-associated beta-galactosidase activity positive cells following UVB exposure in this cell line in contrast to primary keratinocytes, suggesting a role for p16(INK-4a) in UVB-induced senescence. However, we detected sustained DNA damage, prolonged cell cycle arrest, and induction of markers of epidermal differentiation like involucrin and filaggrin as consequences of the repeated exposures. Keratinocytes exposed to the same dose of UVB in a single exposure died. Furthermore, the abundance of the keratins 6, 16 and 17 was increased in keratinocytes exposed repeatedly to UVB suggesting an alternative differentiation. This model allows the induction of a state of differentiation observed in vivo with differentiation uncoupled from premature senescence.
Bertrand-Vallery
Véronique
V
Research Unit of Cellular Biology, Department of Biology, University of Namur, Rue de Bruxelles 61, Namur, Belgium.
Boilan
Emmanuelle
E
Ninane
Noëlle
N
Demazy
Catherine
C
Friguet
Bertrand
B
Toussaint
Olivier
O
Poumay
Yves
Y
Debacq-Chainiaux
Florence
F
D017209:Apoptosis / Q000528:radiation effects; D002453:Cell Cycle / Q000528:radiation effects; D002454:Cell Differentiation / Q000528:radiation effects*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000528:radiation effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D000091344:Filaggrin Proteins; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects*; D007633:Keratins / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D001616:beta-Galactosidase / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D011498:Protein Precursors; D016159:Tumor Suppressor Protein p53; C032253:involucrin; D007633:Keratins; D001616:beta-Galactosidase