Cloning genes responsive to a hepatocarcinogenic peroxisome proliferator chemical reveals novel targets of regulation.
To better understand the molecular basis of the hepatocyte proliferation and induction of hepatocellular adenomas by exposure to peroxisome proliferator chemicals (PPC), a systematic search for genes modulated by a PPC (WY-14643) in rat liver was carried out using the differential display technique. The fragments fell into two classes based on the time of initial and maximal induction by WY-14643. The class I genes (clones 5 and 30) were induced 3 h after a gavage exposure to WY-14643 with maximal expression at 24 h. The class II genes (clones 13 and 16) were induced after 24 h with maximal expression at 78 weeks. Expression of the class II genes was also increased after other treatments that cause cell proliferation. Clone 30 was identified as CYP4A2, previously shown to be regulated by PPC. Clone 13 was homologous to the mouse protein H gene, a component of the heterogeneous nuclear ribonucleoprotein particle important in mRNA splicing. Clone 16 was identified as cyclophilin-A, the receptor for the immunosuppressant drug cyclosporin A. The sequence of clone 5 was unique. These data demonstrate that WY-14643 increases the levels of a number of novel genes that are coordinately regulated with increases in chronic cell proliferation and fatty acid metabolism.
Corton
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JC
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709-2137, USA. corton@ciit.org
Moreno
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ES
Merritt
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A
Bocos
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Cattley
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RC
D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005796:Genes / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase / Q000235:genetics; D020025:Peroxisome Proliferators / Q000009:adverse effects*; D011743:Pyrimidines / Q000009:adverse effects*; D051381:Rats; D011916:Rats, Inbred F344; D017422:Sequence Analysis, DNA; D013997:Time Factors
D018076:DNA, Complementary; D020025:Peroxisome Proliferators; D011743:Pyrimidines; C006253:pirinixic acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D019696:Peptidylprolyl Isomerase