Suppression of albumin and alpha-fetoprotein gene expression by butyrolactone I, a selective inhibitor of the cdk family, in HuH-7 human hepatoma cells.
Butyrolactone I is a selective inhibitor of the cyclin-dependent kinase (cdk) family, cdk2 and cdc2 kinase. In the present study, the effect of butyrolactone I on expression of the albumin and alpha-fetoprotein (AFP) genes was investigated in HuH-7 human hepatoma cells. Butyrolactone I inhibited cell growth and arrested cells predominantly in G2/M phase. By Northern blot analysis, the levels of both albumin and AFP mRNA were suppressed dose-dependently by butyrolactone I. In transient chloramphenicol acetyltransferase plasmid transfection experiments, the albumin promoter activity and the AFP promoter and enhancer activities were suppressed by butyrolactone I. Consistent with this, the transcripts of hepatocyte nuclear factor-1 (HNF-1), a liver-specific transcription factor which transactivates these promoter and enhancer regions were reduced by butyrolactone I in a dose-dependent manner. These results indicate that butyrolactone I down-regulates both the albumin and the AFP gene transcription through the reduction of HNF-1 expression.
Hida
D
D
First Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
Nakata
K
K
Shima
Y
Y
Migita
K
K
Nakao
K
K
Kato
Y
Y
Ishii
N
N
Eguchi
K
K
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000633:toxicity; D006528:Carcinoma, Hepatocellular; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D008113:Liver Neoplasms; D008938:Mitosis; D012333:RNA, Messenger / Q000235:genetics; D012709:Serum Albumin / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D000509:alpha-Fetoproteins / Q000235:genetics*
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D012709:Serum Albumin; D000509:alpha-Fetoproteins; C082868:butyrolactone I; D015500:Chloramphenicol O-Acetyltransferase; D018844:Cyclin-Dependent Kinases; D015107:4-Butyrolactone