Role of peroxisome proliferator-activated receptor alpha in altered cell cycle regulation in mouse liver.
The mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis are unclear but are mediated by the peroxisome proliferator-activated receptor alpha (PPARalpha). To determine the role of PPARalpha in the mechanisms of hepatocarcinogenesis, the effect of Wy-14,643 on expression patterns of acyl CoA oxidase (ACO) and proteins involved in cell proliferation in the PPARalpha-null mouse were evaluated. ACO, CDK-1, CDK-2, CDK-4, PCNA and c-myc proteins were significantly increased in wild-type mice fed Wy-14,643 for 5 weeks or 11 months, as compared with controls. This effect was not observed in Wy-14,643-treated PPARalpha-null mice. Expression patterns of cyclin B1, cyclin D, cyclin E and p53 were not different in any of the groups. mRNAs encoding CDK-1, CDK-4, cyclin D1 and c-myc were also increased in wild-type mice fed Wy-14,643 but not in PPARalpha-null mice. These results indicate that the increase in CDK-1, CDK-4 and c-myc may be caused by an increase in transcription that is mediated directly or indirectly by PPARalpha. Thus PPARalpha-dependent alterations in cell cycle regulatory proteins induced by peroxisome proliferators are likely to contribute to the hepatocarcinogenicity of peroxisome proliferators.
Peters
J M
JM
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. jpeters@helix.nih.gov
Aoyama
T
T
Cattley
R C
RC
Nobumitsu
U
U
Hashimoto
T
T
Gonzalez
F J
FJ
D042962:Acyl-CoA Oxidase; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D018844:Cyclin-Dependent Kinases / Q000032:analysis; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D010088:Oxidoreductases / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D011743:Pyrimidines / Q000633:toxicity*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D020025:Peroxisome Proliferators; D018809:Proliferating Cell Nuclear Antigen; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C006253:pirinixic acid; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase; D018844:Cyclin-Dependent Kinases