p53 may mediate the mdr-1 expression via the WT1 gene in human vincristine-resistant leukemia/lymphoma cell lines.
To investigate the regulatory mechanism of the expression of the multidrug resistance gene (mdr-1) and the multidrug resistance-associated protein gene (mrp), we investigated if p53, WT1, RB, C-myc, N-myc, cyclin D1, p16INK4 (p16) are involved in the acquirement of multidrug resistance phenotype (MDR) in human vincristine (VCR)-resistant cells of leukemia/lymphoma cell lines. By using RT-PCR, we observed that MDR in VCR-resistant cell lines was mediated by either mdr-1 or mrp genes. In cells that acquired the overexpression of mdr-1, downregulation of p53 and upregulation of WT-1 were observed. In contrast, no constant change of genes was observed in cells that overexpressed mrp. Although the change in the expression level of cyclin D1 and p-16 accompanied the development of VCR resistance, the mRNA of RB, C-myc and N-myc showed no correlation with the degree of VCR resistance or the level of mdr-1 expression. These results may provide a plausible diagnostic marker for determination of drug sensitivity in cancer patients and suggest that p53 may mediate directly or indirectly the expression of mdr-1 via WT1 in VCR-resistant hematologic cell lines.
Hirose
M
M
Division of Transfusion Medicine, School of Medicine, The University of Tokushima, Tokushima City, Japan. hirose@clin.med.tokushima-u.ac.jp
Kuroda
Y
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D003561:Cytarabine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016161:Genes, Retinoblastoma / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology; D025721:WT1 Proteins
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D019938:Cyclin D1; D019941:Cyclin-Dependent Kinase Inhibitor p16; D003561:Cytarabine; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014157:Transcription Factors; D014750:Vincristine; D025721:WT1 Proteins