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Chronic Microcystin Exposure Induces Hepatocyte Proliferation with Increased Expression of Mitotic and Cyclin-associated Genes in P53-deficient Mice

¹ Department of Veterinary Pathobiology, Purdue University, West Lafayette, Indiana, USA;
² Lilly Research Laboratories, Department of Investigative Toxicology, Eli Lilly and Company, Greenfield, Indiana, USA

Correspondence: Address correspondence to: Dr. Shawn P. Clark, Bristol-Myers Squibb Company, Pharmaceutical Research Institute, 2400 W Lloyd Expressway (P3), Evansville, IN 47721; e-mail: shawn.clark{at}bms.com.

Homozygous p53 deficient knockout mice were used to assess the role of p53 in tumor promotion by the protein phosphatase inhibitor and hepatic tumor promoter microcystin-LR (MCLR). More than 50% of human cancers bear mutations in the p53 gene, and in particular, p53 tumor suppressor gene mutations have been shown to play a major role in hepatocarcinogenesis. Trp53 homozygous (inactivated p53) and age-matched wild-type control mice were assigned to vehicle or MCLR-treated groups. MCLR or saline was administered daily for up to 28 days. RNA from the 28-day study was hybridized onto Mouse Genome GeneChip arrays. Selected RNA from 28 days and earlier time points was also processed for quantitative polymerase chain reaction (PCR). Livers from the 28-day, Trp53-deficient, MCLR group displayed greater hyperplastic and dysplastic changes morphologically and increases in Ki-67 and phosphohistone H3 (mitotic marker) immunoreactivity. Gene-expression analysis revealed significant increases in expression of cell-cycle regulation and cellular proliferation genes in the MCLR-treated, p53-deficient mutant mice compared to controls. These data suggest that regulation of the cell cycle by p53 is important in preventing the proliferative response associated with chronic, sublethal microcystin exposure, and therefore, conclude that p53 plays an important role in MCLR-induced tumor promotion.

Key Words: Microcystin-LR • p53 • p53-deficient mice • microarray • liver • tumorigenesis • protein phosphatase • morphology • cell cycle • mitosis • cell proliferation

Abbreviations: ALP, alkaline phosphatase • ALT, alanine aminotransferase • AST, aspartate aminotransferase • DAB, diaminobenzidine • GGT, gamma glutamyltransferase • H&E, hematoxylin and eosin • MCLR, microcystin-LR • PCR, polymerase chain reaction • PP, protein phosphatase

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