The inhibitory effect of the proinflammatory cytokine TNFalpha on erythroid differentiation involves erythroid transcription factor modulation.
The hematopoietic transcription factor GATA-1 regulates the expression of several genes associated with differentiation of erythroid cells. We show here the inhibitory effect of tumor necrosis factor alpha (TNFalpha), a proinflammatory cytokine, on hemoglobinization and erythroid transcription factor GATA-1 expression in erythroleukemia (HEL) as well as in chronic myelogenous leukemia (K562) cells, which were induced to differentiate towards the erythroid lineage after aclacinomycin (Acla), doxorubicin (Dox) or hemin (HM) treatment. As a result, we observed i) a decreased expression of Friend of GATA-1 (FOG-1), an essential cofactor of GATA-1 transcription factor, ii) a downregulation of GATA-1 by proteasomal degradation and iii) a reduced acetylation level of GATA-1 in HM-induced K562 cells after TNF treatment. As a result, these modifications i) decreased the level of GATA-1/FOG-1 complex, ii) unsettled the GATA-1/GATA-2 balance, iii) reduced GATA-1 transcriptional activity and iv) inhibited erythroid marker gene expression (glycophorin A, erythropoietin receptor, gamma-globin) independently of the cell line or the inducer used. These data provided new insights into the role of GATA-1 regulation in TNFalpha-mediated inhibition of erythroid differentiation in erythroleukemia.
Buck
Isabelle
I
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, L-2540 Luxemburg, Luxemburg.
Morceau
Franck
F
Cristofanon
Silvia
S
Reuter
Simone
S
Dicato
Mario
M
Diederich
Marc
M
D015250:Aclarubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D041905:Erythroid Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050982:GATA1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D006427:Hemin / Q000494:pharmacology; D006454:Hemoglobins / Q000096:biosynthesis; D006801:Humans; D020014:K562 Cells; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D050982:GATA1 Transcription Factor; D006454:Hemoglobins; D009687:Nuclear Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C498432:ZFPM1 protein, human; C011157:aclacinomycins; D006427:Hemin; D015250:Aclarubicin; D004317:Doxorubicin