Additive roles of XPA and MSH2 genes in UVB-induced skin tumorigenesis in mice.
We have made xeroderma pigmentosum group A gene (XPA)-knockout mice (XPA(-/-) mice). The XPA(-/-) mice had no detectable activity for nucleotide excision repair (NER) and showed a high incidence of UVB-induced skin tumorigenesis. We have also found that cell lines derived from skin cancers in UVB-irradiated XPA(-/-) mice become tolerant to UV-irradiation and showed abnormal UV-induced cell cycle checkpoints and decreased mismatch repair (MMR) activity. These results suggested that the MMR-downregulation may help cells escape killing by UV-irradiation and thus MMR-deficient clones are selected for during the tumorigenic transformation of XPA(-/-) cells. In this report, we examined whether the incidence of UVB-induced skin tumorigenesis is enhanced in XPA(-/-)MSH2(-/-), XPA(-/-) and MSH2(-/-) mice when compared with that in wild-type mice. Our results indicate that the MSH2-deficiency caused a high incidence of spontaneous and UVB-induced skin tumorigenesis and the XPA and MSH2 genes have additive roles in the UV-induced skin tumorigenesis.
Yoshino
Masafumi
M
Laboratories of Organismal Biosystems, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Japan.
Nakatsu
Yoshimichi
Y
te Riele
Hein
H
Hirota
Seiichi
S
Kitamura
Yukihiko
Y
Tanaka
Kiyoji
K
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology*; D012867:Skin / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D015996:Survival Rate; D014466:Ultraviolet Rays / Q000009:adverse effects; D051760:Xeroderma Pigmentosum Group A Protein
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein