Expression of CAR in SW480 and HepG2 cells during G1 is associated with cell proliferation.
Constitutive androstane receptor (CAR) is a transcription factor to regulate the expression of several genes related to drug-metabolism. Here, we demonstrate that CAR protein accumulates during G1 in human SW480 and HepG2 cells. After the G1/S phase transition, CAR protein levels decreased, and CAR was hardly detected in cells by the late M phase. CAR expression in both cell lines was suppressed by RNA interference-mediated suppression of CDK4. Depletion of CAR by RNA interference in both cells and by hepatocyte growth factor treatment in HepG2 cells resulted in decreased MDM2 expression that led to p21 upregulation and repression of HepG2 cell growth. Thus, our results demonstrate that CAR expression is an early G1 event regulated by CDK4 that contributes to MDM2 expression; these findings suggest that CAR may influence the expression of genes involved in not only the metabolism of endogenous and exogenous substances but also in the cell proliferation.
Osabe
Makoto
M
Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Sugatani
Junko
J
Takemura
Akiko
A
Yamazaki
Yasuhiro
Y
Ikari
Akira
A
Kitamura
Naomi
N
Negishi
Masahiko
M
Miwa
Masao
M
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics*; D015870:Gene Expression; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D012697:Serine Endopeptidases / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000099148:UGT1A1 Enzyme
D000090702:Constitutive Androstane Receptor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D014453:Glucuronosyltransferase; D051736:Proto-Oncogene Proteins c-mdm2; D018160:Receptors, Cytoplasmic and Nuclear; D012697:Serine Endopeptidases; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000099148:UGT1A1 Enzyme; C493956:CDKN1A protein, human; C497206:MDM2 protein, human; C081092:HGF activator