Aberrant activation of ubiquitin D at G<sub>2</sub> phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats

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  • Taniai Eriko
    Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
  • Yafune Atsunori
    Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University Gotemba Laboratory, Bozo Research Center Inc.
  • Hayashi Hitomi
    Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
  • Itahashi Megu
    Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
  • Hara-Kudo Yukiko
    Division of Microbiology, National Institute of Health Sciences
  • Suzuki Kazuhiko
    Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology
  • Mitsumori Kunitoshi
    Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology
  • Shibutani Makoto
    Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology

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  • Aberrant activation of ubiquitin D at G₂ phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats

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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 G2 phase and increased apoptosis reflecting aberrant cell cycle regulation may be the common feature of these carcinogens.

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