title: Aberrant activation of ubiquitin D at G2 phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats.
abstract: We have previously reported that renal carcinogens examined in rats increase tubular cell proliferation and topoisomerase (Topo) IIα(+) cells. The present study was aimed at identifying early prediction markers of carcinogens after 28-day treatment in rats. Following gene expression screening by microarrays in renal tubules with renal carcinogens, immunohistochemical analysis and TUNEL-assay were performed with carcinogens targeting different organs. All renal carcinogens tested (ferric nitrilotriacetic acid, ochratoxin A (OTA), monuron, tris(2-chloroethyl) phosphate, and potassium bromate) increased tubular cells immunoreactive for minichromosome maintenance 3 (Mcm3) or ubiquitin D (Ubd) or those showing apoptosis, compared with untreated controls or non-carcinogenic renal toxicants. Carcinogens targeting the liver (thioacetamide (TAA), fenbendazole, piperonyl butoxide (PBO) and methyleugenol), thyroid (sulfadimethoxine), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole), glandular stomach (catechol), and colon (chenodeoxycholic acid and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) were examined for induction of Mcm3, Ubd, Topo IIα, Ki-67 and apoptosis using non-carcinogenic toxicants as negative controls. All carcinogens increased Mcm3(+), Ubd(+), Topo IIα(+), Ki-67(+) or TUNEL(+) cells, except for hepatocarcinogen PBO and both colon carcinogens, which did not increase cell proliferation. Ubd(+) cells co-expressing Topo IIα was increased without changing phospho-Histone H3-co-expressing cell population as examined with OTA and TAA. Results revealed cooperative responses of Topo IIα, Ubd and apoptosis by carcinogens inducing high proliferation activity, irrespective of target organs, examined here after a 28-day administration. Aberrant expression of Ubd at G(2) phase and increased apoptosis reflecting aberrant cell cycle regulation may be the common feature of these carcinogens.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Taniai
authors.forename: Atsunori
authors.initials: A
authors.lastname: Yafune
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Megu
authors.initials: M
authors.lastname: Itahashi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hara-Kudo
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; D000951:Antigens, Neoplasm / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D016195:G2 Phase / Q000235:genetics* / Q000502:physiology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D002273:Carcinogens; D004268:DNA-Binding Proteins; C109184:UBD protein, human; D014452:Ubiquitins; D004250:DNA Topoisomerases, Type II