Induction of minisatellite mutation in NIH 3T3 cells by treatment with the tumor promoter okadaic acid.
Okadaic acid (OA) is a strong tumor promoter of mouse skin carcinogenesis and also a potent inhibitor of serine/threonine protein phosphatases. OA induces various genetic alterations in cultured cells, such as diphtheria-toxin-resistance mutations, sister chromatid exchange, exclusion of exogenous transforming oncogenes, and gene amplification. The present study revealed that it caused minisatellite mutation (MSM) at a high frequency in NIH 3T3 cells, although no microsatellite mutation was found. Nine of 31 clones (29%) exhibited MSM after 6 days of OA treatment, as opposed to only 1 of 30 clones (3%) without OA exposure. Moreover, NIH 3T3 cells treated with OA acquired tumorigenicity in nude mice, giving rise to 7 tumors within 25 weeks in 20 sites where 3 x 10(6) cells were injected. In contrast, the same numbers of untreated cells gave rise to only one tumor, and the tumor grew much slower. All of three OA-induced tumors examined manifested the MSM. The findings thus point to a molecular mechanism by which OA could function as a tumor promoter, and also the biological relevance of the induction of MSM in the tumorigenic process by OA.
Nakagama
H
H
Biochemistry, National Cancer Center Research Institute, 1-1, Tsukiji 5, Chuo-ku, Tokyo 104, Japan.
Kaneko
S
S
Shima
H
H
Inamori
H
H
Fukuda
H
H
Kominami
R
R
Sugimura
T
T
Nagao
M
M
D016475:3T3 Cells; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D003001:Cloning, Molecular; D016172:DNA Fingerprinting; D004260:DNA Repair; D004276:DNA, Satellite / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009153:Mutagens / Q000494:pharmacology*; D019319:Okadaic Acid / Q000494:pharmacology*; D019680:Trinucleotide Repeat Expansion; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D004276:DNA, Satellite; D009153:Mutagens; D019319:Okadaic Acid