p53 and Fas ligand are required for psoralen and UVA-induced apoptosis in mouse epidermal cells.
A combination of 8-methoxypsoralen (8-MOP) and ultraviolet-A (UVA) radiation (320-400 nm) (PUVA) is widely used in the treatment of psoriasis and other skin diseases. PUVA is highly effective in eliminating hyperproliferative cells in the epidermis, but its mechanism of action has not been fully elucidated. In this study, we used immortalized JB6 mouse epidermal cells, p53(-/-), and Fas ligand deficient (gld) mice to investigate the molecular mechanism by which PUVA induces cell death. The results indicate that PUVA treatment induces apoptosis in JB6 cells. In addition, PUVA treatment of JB6 cells results in p53 stabilization, phosphorylation, and nuclear localization as well as induction of p21(Waf/Cip1) and caspase-3 activity. In vivo studies reveal that PUVA treatment induces significantly less apoptosis in the epidermis of p53(-/-) mice compared to p53(+/+) mice. Furthermore, FasL-deficient (gld) mice are completely resistant to PUVA-induced apoptosis compared to wild-type mice. These results indicate that PUVA treatment induces apoptosis in mouse epidermal cells in vitro and in vivo and that p53 and Fas/Fas ligand interactions are required for this process, at least in vivo. This implies that similar mechanisms may be involved in the elimination of psoriatic keratinocytes from human skin following PUVA therapy.
Santamaria
A B
AB
Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Davis
D W
DW
Nghiem
D X
DX
McConkey
D J
DJ
Ullrich
S E
SE
Kapoor
M
M
Lozano
G
G
Ananthaswamy
H N
HN
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000528:radiation effects; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004789:Enzyme Activation; D004817:Epidermis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008730:Methoxsalen / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D008730:Methoxsalen