Tumor necrosis factor alpha inhibits aclacinomycin A-induced erythroid differentiation of K562 cells via GATA-1.
Up-regulation of tumor necrosis factor alpha (TNFalpha) is linked to solid tumors as well as to hematologic disorders including different forms of anemia and multiple myeloma. This cytokine was shown to contribute to inhibition of erythroid maturation mechanisms which are characterized by the expression of specific genes regulated by GATA-1 and NF-E2 transcription factors. Here, we assessed the inhibiting effect of TNFalpha on erythroid differentiation using K562 cells which can be chemically induced to differentiate towards the erythroid pathway by aclacinomycin A, an anthracyclin. Results show that induced hemoglobinization of K562 cells as well as gamma-globin and erythropoietin receptor gene expression are decreased by TNFalpha via the inhibition of GATA-1 at its mRNA and protein expression level. Additionally, both constitutive and induced binding activity of GATA-1 is abolished and induced activation of a GATA-1 driven luciferase reporter construct is inhibited. Altogether, our results provide insight into the molecular mechanisms of inflammation-induced inhibition of erythroid differentiation.
Morceau
Franck
F
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9 rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
Schnekenburger
Michael
M
Blasius
Romain
R
Buck
Isabelle
I
Dicato
Mario
M
Diederich
Marc
M
D015250:Aclarubicin / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D024202:Electrophoretic Mobility Shift Assay; D015672:Erythroid Precursor Cells / Q000187:drug effects*; D050982:GATA1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005914:Globins / Q000378:metabolism; D006801:Humans; D020014:K562 Cells / Q000187:drug effects; D008156:Luciferases / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D014409:Tumor Necrosis Factor-alpha; D015250:Aclarubicin; D005914:Globins; D008156:Luciferases