E. coli gpt gene expression effects on K562 human leukemia cell proliferation and erythroid differentiation altered by mycophenolic acid.
Inosine monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) inhibitors including mycophenolic acid (MPA) were reported to induce K562 human leukemia cells to differentiate into erythroid cells. A shuttle vector plasmid pMSG containing E. coli xanthine-guanine phosphoribosyl transferase (Eco gpt) gene was transfected into K562 cells (K562-pMSG cells) to investigate the role of IMPDH in both K562 cell proliferation and erythroid differentiation. Eco gpt provides K562 cells with an additional salvage pathway for GMP production from xanthine. In the presence of xanthine, K562-pMSG cells continued to proliferate and did not differentiate to erythroid cells regardless of the presence of MPA, but they discontinued proliferating and differentiated into the erythroid lineage in the absence of xanthine. Proliferation and differentiation of control K562 cells into erythroid cells were suppressed by MPA regardless of the presence or absence of xanthine. Addition of guanosine maintained the proliferation and blocked the erythroid differentiation of K562 and K562-pMSG cells induced by MPA even in the absence of xanthine. These data indicate that a decrease in the activity of IMPDH and a subsequent decline in the concentration of guanine nucleotides caused by MPA resulted in the induction of the erythroid differentiation and discontinuation of the proliferation of K562 cells.
Kamano
H
H
First Department of Internal Medicine, Kagawa Medical School, Japan.
Tanaka
T
T
Yamaji
Y
Y
Ikeda
K
K
Hata
Y
Y
Shiotani
T
T
Ishida
T
T
Takahara
J
J
Irino
S
S
D015139:Blotting, Southern; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D004912:Erythrocytes / Q000166:cytology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D007938:Leukemia; D009173:Mycophenolic Acid / Q000494:pharmacology*; D010430:Pentosyltransferases / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D007168:IMP Dehydrogenase; D010430:Pentosyltransferases; C024827:xanthine phosphoribosyltransferase; D009173:Mycophenolic Acid