3'-Azido-3'-deoxythymidine inhibits erythroid-specific transcription factors in human erythroid K562 leukemia cells.
The present study examines genetic mechanism(s) possibly involved in the observed 3'-azido-3'-deoxythymidine (AZT)-induced inhibition of globin gene transcription by evaluating the direct phenotypic erythroid effects of AZT on erythroid-specific transcription factors which regulate globin gene promoters. In vitro binding of GATA-1 or NFE-2 to its consensus sequence was decreased in the presence of AZT reaching a maximum inhibition as early as 24 h after AZT treatment. Nuclear extracts from butyric acid-induced K562 cells treated with an IC50 concentration of AZT exhibited a decrease in GATA-1 and NFE-2 binding by approximately 30% and 35%. In contrast, 2',3'-dideoxycytidine which inhibits cell growth without affecting hemoglobin synthesis, had no effect on binding of GATA-1 and NFE-2 factors. Northern blot analysis revealed a 25% decrease by AZT in GATA-1 mRNA steady-state levels at 24 h and this inhibitory effect was maintained until 72 h after drug addition. A similar decrease in NFE-2 mRNA steady-state levels was observed at 72 h after AZT treatment. This study suggests that AZT inhibition of erythroid differentiation is subsequent to a decrease of nuclear factors gene expression which affect their DNA binding.
Bridges
E G
EG
Department of Pharmacology and Toxicology, Center for AIDS Research and the Comprehensive Cancer Center, University of Alabama at Birmingham, USA.
Trentesaux
C
C
Lahlil
R
R
Spiga
M G
MG
Jeannesson
P
P
Sommadossi
J P
JP
D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D005914:Globins / Q000235:genetics; D006454:Hemoglobins / Q000096:biosynthesis; D051863:Host Cell Factor C1; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics; D004915:Leukemia, Erythroblastic, Acute; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D050811:Octamer Transcription Factor-1; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D016047:Zalcitabine / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology*
D000998:Antiviral Agents; D002087:Butyrates; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C497692:HCFC1 protein, human; D006454:Hemoglobins; D051863:Host Cell Factor C1; D009687:Nuclear Proteins; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D014157:Transcription Factors; D020148:Butyric Acid; D015215:Zidovudine; D016047:Zalcitabine; D005914:Globins; D011163:Hydroxymethylbilane Synthase