Specific allelic loss of p16 (INK4A) tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis.
Oxidative tissue damage has been shown to be associated with carcinogenesis. In human cancers p16(INK4A) is one of the most frequently mutated tumor suppressor genes. The present study used the ferric nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis model to determine whether oxidative damage can cause specific allelic loss of p16 (INK4A). By the use of fluorescent in situ hybridization in combination with imprint cytology at single-cell resolution, we found that the number of renal tubular cells with aneuploidy (1 or 3 signals) at the p16(INK4A) locus was significantly and specifically increased (1 week, 37.2 +/- 2.3%; 3 weeks, 37.8 +/- 1.3% vs control, 22.5 +/- 1.9%; mean +/- SE, N = 8; P < 0.001 and P < 0.0001, respectively) after repeated intraperitoneal administration of 5 to10 mg of iron/kg in the form of Fe-NTA for 3 weeks. No increase in aneuploidy was observed at the loci of either the p53 or vhl tumor suppressor gene. Furthermore, the increase in the cells with 3 signals was followed by a continuous increase in those with 1 signal. Therefore, the p16 (INK4A) locus is specifically vulnerable to oxidative damage, leading to its allelic loss within weeks, presumably due to a deficiency in the replication of both the alleles.
Hiroyasu
Makoto
M
Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Ozeki
Munetaka
M
Kohda
Haruyasu
H
Echizenya
Michiko
M
Tanaka
Tomoyuki
T
Hiai
Hiroshi
H
Toyokuni
Shinya
S
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D005290:Ferric Compounds / Q000633:toxicity; D016147:Genes, Tumor Suppressor; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007501:Iron / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
D002273:Carcinogens; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005290:Ferric Compounds; D007501:Iron; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate