Serpin squamous cell carcinoma antigen inhibits UV-induced apoptosis via suppression of c-JUN NH2-terminal kinase.
Protection from ultraviolet (UV) irradiation is a fundamental issue for living organisms. Although melanin's critical role in the protection of basal keratinocytes is well understood, other factors remain essentially unknown. We demonstrate that up-regulation of squamous cell carcinoma antigen-1 (SCCA1) suppresses c-Jun NH2-terminal kinase-1 (JNK1) and thus blocks UV-induced keratinocyte apoptosis. We found that serpin SCCA1 is markedly elevated in the top layers of sun-exposed or UV-irradiated epidermis. UV-induced apoptosis was significantly decreased when SCCA was overexpressed in 3T3/J2 cells. It was significantly increased when SCCA was down-regulated with small interfering RNA in HaCaT keratinocytes. A search for SCCA-interacting molecules showed specific binding with phosphorylated JNK. Interestingly, SCCA1 specifically suppressed the kinase activity of JNK1. Upon exposure of keratinocytes to UV, SCCA1 was bound to JNK1 and transferred to the nucleus. Involucrin promoter-driven SCCA1 transgenic mice showed remarkable resistance against UV irradiation. These findings reveal an unexpected serpin function and define a novel UV protection mechanism in human skin.
Shiseido Life Science Research Center, Yokohama 236-8643, Japan.
Chika
C
Katagiri
Jotaro
J
Nakanishi
Kuniko
K
Kadoya
Toshihiko
T
Hibino
D016475:3T3 Cells; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D003593:Cytoplasm / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000502:physiology; D011498:Protein Precursors / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000528:radiation effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015843:Serpins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D014162:Transfection; D014466:Ultraviolet Rays
D000951:Antigens, Neoplasm; D010446:Peptide Fragments; D011498:Protein Precursors; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D015843:Serpins; C051072:squamous cell carcinoma-related antigen; C032253:involucrin; D048055:Mitogen-Activated Protein Kinase 8