Inhibition of beta-globin gene expression by 3'-azido-3'-deoxythymidine in human erythroid progenitor cells. 1999

M G Spiga, and D A Weidner, and C Trentesaux, and R D LeBoeuf, and J P Sommadossi
Department of Biochemistry and Molecular Biology, School of Medicine, University of Miami, FL 33136, USA.

3'-Azido-3'-deoxythymidine (AZT) treatment in HIV-infected patients is limited by bone marrow suppression including neutropenia and anemia. Previous studies had shown a direct effect of high concentrations of this drug on globin gene expression in K-562 erythroleukemia cells. To better define the mechanism(s) of AZT-induced bone marrow toxicity, the present study evaluates these effects in more relevant human erythroid progenitor liquid cultures, because AZT is 100 times more toxic to human bone marrow cells than K-562 cells. At a clinically relevant concentration of 1 microM, AZT inhibited specifically erythroid cell growth by approximately 58% as compared with untreated cells. The percentage of cells synthesizing hemoglobin was decreased also by 47% in AZT-treated cells with beta-globin mRNA levels accounting for 0.27 pmol in treated cells as compared with 1.44 under control conditions while beta-actin levels remained unchanged. Under the same conditions, AZT inhibited the beta-globin chain synthesis by approximately 60% as compared with the control. Consistent with the data described above was the finding that a concentration as low as 0.1 microM of AZT decreased by almost 40% the binding level of the erythroid-specific transcription factor GATA-1. These findings demonstrate that AZT, at clinical relevant concentrations, specifically inhibits beta-globin gene expression in human erythroid progenitor liquid cell culture.

UI MeSH Term Description Entries
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004268 DNA-Binding Proteins Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases. DNA Helix Destabilizing Proteins,DNA-Binding Protein,Single-Stranded DNA Binding Proteins,DNA Binding Protein,DNA Single-Stranded Binding Protein,SS DNA BP,Single-Stranded DNA-Binding Protein,Binding Protein, DNA,DNA Binding Proteins,DNA Single Stranded Binding Protein,DNA-Binding Protein, Single-Stranded,Protein, DNA-Binding,Single Stranded DNA Binding Protein,Single Stranded DNA Binding Proteins
D005914 Globins A superfamily of proteins containing the globin fold which is composed of 6-8 alpha helices arranged in a characterstic HEME enclosing structure. Globin
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000199 Actins Filamentous proteins that are the main constituent of the thin filaments of muscle fibers. The filaments (known also as filamentous or F-actin) can be dissociated into their globular subunits; each subunit is composed of a single polypeptide 375 amino acids long. This is known as globular or G-actin. In conjunction with MYOSINS, actin is responsible for the contraction and relaxation of muscle. F-Actin,G-Actin,Actin,Isoactin,N-Actin,alpha-Actin,alpha-Isoactin,beta-Actin,gamma-Actin,F Actin,G Actin,N Actin,alpha Actin,alpha Isoactin,beta Actin,gamma Actin
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
D014157 Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Transcription Factor,Factor, Transcription,Factors, Transcription
D014158 Transcription, Genetic The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION. Genetic Transcription
D015215 Zidovudine A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIV-induced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. AZT (Antiviral),Azidothymidine,3'-Azido-2',3'-Dideoxythymidine,3'-Azido-3'-deoxythymidine,AZT Antiviral,AZT, Antiviral,BW A509U,BWA-509U,Retrovir,3' Azido 2',3' Dideoxythymidine,3' Azido 3' deoxythymidine,Antiviral AZT,BWA 509U,BWA509U
D015672 Erythroid Precursor Cells The cells in the erythroid series derived from MYELOID PROGENITOR CELLS or from the bi-potential MEGAKARYOCYTE-ERYTHROID PROGENITOR CELLS which eventually give rise to mature RED BLOOD CELLS. The erythroid progenitor cells develop in two phases: erythroid burst-forming units (BFU-E) followed by erythroid colony-forming units (CFU-E); BFU-E differentiate into CFU-E on stimulation by ERYTHROPOIETIN, and then further differentiate into ERYTHROBLASTS when stimulated by other factors. Burst-Forming Units, Erythroid,Colony-Forming Units, Erythroid,Erythroid Progenitor Cells,Erythropoietic Progenitor Cells,Erythropoietic Stem Cells,Progenitor Cells, Erythropoietic,Stem Cells, Erythroid,BFU-E,CFU-E,BFU E,BFU-Es,Burst Forming Units, Erythroid,Burst-Forming Unit, Erythroid,CFU E,CFU-Es,Cell, Erythroid Precursor,Cell, Erythroid Progenitor,Cell, Erythroid Stem,Cell, Erythropoietic Progenitor,Cell, Erythropoietic Stem,Cells, Erythroid Precursor,Cells, Erythroid Progenitor,Cells, Erythroid Stem,Cells, Erythropoietic Progenitor,Cells, Erythropoietic Stem,Colony Forming Units, Erythroid,Colony-Forming Unit, Erythroid,Erythroid Burst-Forming Unit,Erythroid Burst-Forming Units,Erythroid Colony-Forming Unit,Erythroid Colony-Forming Units,Erythroid Precursor Cell,Erythroid Progenitor Cell,Erythroid Stem Cell,Erythroid Stem Cells,Erythropoietic Progenitor Cell,Erythropoietic Stem Cell,Precursor Cell, Erythroid,Precursor Cells, Erythroid,Progenitor Cell, Erythroid,Progenitor Cell, Erythropoietic,Progenitor Cells, Erythroid,Stem Cell, Erythroid,Stem Cell, Erythropoietic,Stem Cells, Erythropoietic,Unit, Erythroid Burst-Forming,Unit, Erythroid Colony-Forming,Units, Erythroid Burst-Forming,Units, Erythroid Colony-Forming

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