title: Aberrant activation of M phase proteins by cell proliferation-evoking carcinogens after 28-day administration in rats.
abstract: We have previously reported that hepatocarcinogens increase liver cells expressing p21(Cip1), a G1 checkpoint protein and M phase proteins after 28-day treatment in rats. This study aimed to identify early prediction markers of carcinogens available in many target organs after 28-day treatment in rats. Immunohistochemical analysis was performed on Ki-67, p21(Cip1) and M phase proteins [nuclear Cdc2, phospho-Histone H3 (p-Histone H3), Aurora B and heterochromatin protein 1α (HP1α)] with carcinogens targeting different organs. Carcinogens targeting thyroid (sulfadimethoxine; SDM), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole; BHA), glandular stomach (catechol; CC), and colon (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and chenodeoxycholic acid) were examined using a non-carcinogenic toxicant (caprolactam) and carcinogens targeting other organs as negative controls. All carcinogens increased Ki-67(+), nuclear Cdc2(+), p-Histone H3(+) or Aurora B(+) carcinogenic target cells, except for both colon carcinogens, which did not increase cell proliferation. On the other hand, p21(Cip1+) cells increased with SDM and CC. HP1α responded only to BHA. Results revealed carcinogens evoking cell proliferation concurrently induced cell cycle arrest at M phase or showing chromosomal instability reflecting aberration in cell cycle regulation, irrespective of target organs, after 28-day treatment. Therefore, M phase proteins may be early prediction markers of carcinogens evoking cell proliferation in many target organs.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, 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: Hitomi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
mesh_terms: D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D015415:Biomarkers / Q000032:analysis; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D016203:CDC2 Protein Kinase; D002273:Carcinogens / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000032:analysis; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis; D018844:Cyclin-Dependent Kinases; D006657:Histones / Q000032:analysis; D007093:Imidazoles / Q000494:pharmacology; D017879:Isothiocyanates / Q000494:pharmacology; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013412:Sulfadimethoxine / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D002273:Carcinogens; D002396:Catechols; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D007093:Imidazoles; D017879:Isothiocyanates; D011725:Pyridines; D000090266:Chromobox Protein Homolog 5; C077584:2-amino-1-methyl-6-(4-hydroxyphenyl)imidazo(4,5-b)pyridine; D002083:Butylated Hydroxyanisole; D013412:Sulfadimethoxine; C058305:phenethyl isothiocyanate; C576925:Aurkb protein, rat; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C548796:Cdk1 protein, rat; D018844:Cyclin-Dependent Kinases; C034221:catechol