p53 haploinsufficiency profoundly accelerates the onset of tongue tumors in mice lacking the xeroderma pigmentosum group A gene.
Mice lacking the xeroderma pigmentosum group A gene (XPA-/- mice), which have a complete deficiency in nucleotide excision repair (NER), are highly predisposed to tongue squamous cell carcinoma (SCC) when exposed to 4-nitroquinoline 1-oxide (4NQO). To explore the effects of the interaction of the NER machinery with p53 in oral tumorigenesis, we generated an XPA-/- mouse strain carrying mutant alleles for p53. This mouse model of 4NQO carcinogenesis demonstrated that despite the same tumor frequency, XPA-/-p53+/- mice reached 100% SCC incidence at 25 weeks compared with 50 weeks for XPA-/-p53+/+ littermates. XPA-/-p53-/- mice succumbed to spontaneous thymic lymphomas before the development of tongue tumors (before 13 weeks of age). SCC originated in XPA-/-p53+/- mice maintained the p53+/- genotype and the retained wild-type p53 allele appeared to be structurally intact. Only one of 20 XPA-/-p53+/+ SCC showed a missense mutation of p53. Collectively, the accelerated tongue tumor growth may be a consequence of haploinsufficiency but not of mutation of p53 in the context of NER deficiency.
Department of Oral Pathology, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283, Japan. idef@dent.meikai.ac.jp
Fumio
F
Ide
Munenori
M
Kitada
Hideaki
H
Sakashita
Kaoru
K
Kusama
Kiyoji
K
Tanaka
Takatoshi
T
Ishikawa
D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000818:Animals; D015139:Blotting, Southern; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D016158:Genes, p53; D005838:Genotype; D008223:Lymphoma / Q000139:chemically induced / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D013953:Thymus Neoplasms / Q000139:chemically induced / Q000235:genetics; D014062:Tongue Neoplasms / Q000139:chemically induced / Q000235:genetics*; D051760:Xeroderma Pigmentosum Group A Protein
D002273:Carcinogens; D004268:DNA-Binding Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D015112:4-Nitroquinoline-1-oxide