title: Immunohistochemical cellular distribution of proteins related to M phase regulation in early proliferative lesions induced by tumor promotion in rat two-stage carcinogenesis models.
abstract: We have previously reported that 28-day treatment with hepatocarcinogens increases liver cells expressing p21(Cip1), a G1/S checkpoint protein, and M phase proteins, i.e., nuclear Cdc2, Aurora B, phosphorylated-Histone H3 (p-Histone H3) and heterochromatin protein 1α (HP1α), in rats. To examine the roles of these markers in the early stages of carcinogenesis, we investigated their cellular distribution in several carcinogenic target organs using rat two-stage carcinogenesis models. Promoting agents targeting the liver (piperonyl butoxide and methapyrilene hydrochloride), thyroid (sulfadimethoxine), urinary bladder (phenylethyl isothiocyanate), and forestomach and glandular stomach (catechol) were administered to rats after initiation treatment for the liver with N-diethylnitrosamine, thyroid with N-bis(2-hydroxypropyl)nitrosamine, urinary bladder with N-butyl-N-(4-hydroxybutyl)nitrosamine, and forestomach and glandular stomach with N-methyl-N'-nitro-N-nitrosoguanidine. Numbers of cells positive for nuclear Cdc2, Aurora B, p-Histone H3 and HP1α increased within preneoplastic lesions as determined by glutathione S-transferase placental form in the liver or phosphorylated p44/42 mitogen-activated protein kinase in the thyroid, and hyperplastic lesions having no known preneoplastic markers in the urinary bladder, forestomach and glandular stomach. Immunoreactive cells for p21(Cip1) were decreased within thyroid preneoplastic lesions; however, they were increased within liver preneoplastic lesions and hyperplastic lesions in other organs. These results suggest that M phase disruption commonly occur during the formation of preneoplastic lesions and hyperplastic lesions. Differences in the expression patterns of p21(Cip1) between thyroid preneoplastic and proliferative lesions in other organs may reflect differences in cell cycle regulation involving G1/S checkpoint function between proliferative lesions in each organ.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Yafune
authors.forename: Eriko
authors.initials: E
authors.lastname: Taniai
authors.forename: Reiko
authors.initials: R
authors.lastname: Morita
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Akane
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kimura
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity; D002455:Cell Division / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D009369:Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D011230:Precancerous Conditions / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013964:Thyroid Neoplasms / Q000139:chemically induced / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000378:metabolism
chemical_list: D002273:Carcinogens; D050759:Cyclin-Dependent Kinase Inhibitor p21
keywords: Carcinogen; M phase; Rat; Two-stage carcinogenesis model; p21(Cip1)