PPARalpha-dependent activation of cell cycle control and DNA repair genes in hepatic nonparenchymal cells.
Peroxisome proliferator-activated receptor-α (PPARα) mediates the diverse biological effects of peroxisome proliferator (PP) chemicals, including fatty acid catabolism, hepatomegaly, hepatocyte proliferation, and hepatocarcinogenesis in rodents. However, transgenic mice expressing a constitutively active PPARα in hepatocytes (VP16PPARα) do not develop hepatocellular carcinomas in spite of hepatocyte proliferation and hepatomegaly; this suggests that activation of genes in nonparenchymal cells may have a critical role in PP-induced carcinogenesis. VP16PPARα mice exhibited massive peroxisome proliferation and hepatomegaly as well as increased mortality upon Wy-14,643 treatment. Several genes involved in cell cycle or DNA damage repair, such as Chek1, Prkdc, Mcm, and Rad51, were significantly induced to a similar extent between wild-type and VP16PPARα mice after Wy-14,643 administration. This induction was completely abolished in Pparα-null mice, suggesting a PPARα-dependent pathway. These data revealed a DNA damage response signaling network as an early event upon PP treatment and provide novel putative mechanisms for PP-induced hepatocellular carcinoma.
Qu
Aijuan
A
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Shah
Yatrik M
YM
Matsubara
Tsutomu
T
Yang
Qian
Q
Gonzalez
Frank J
FJ
D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006529:Hepatomegaly / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; C006253:pirinixic acid
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