GTP-mediated differentiation of the human K562 cell line: transient overexpression of GATA-1 and stabilization of the gamma-globin mRNA.
Induction of specific gene expression may provide an alternative or a support to conventional cytotoxic chemotherapy of cancer, as well as to therapy for sickle cell diseases. In this respect, pharmacological induction of expression of the endogenous gamma-globin gene is a realistic approach to therapy of beta-globin disorders. Erythroid differentiation and inhibition of proliferation of the human CML K562 cell line was induced by guanosine 5'-triphosphate (GTP). The hemoglobin production in cells was correlated to an increase in alpha- and gamma-globin mRNA expression. At the transcriptional level, we showed that both the expression of the major erythroid transcription factor GATA-1 (protein and mRNA) and its binding capacity to the gamma-globin gene promoter was transiently increased. Moreover, GTP moderately stimulated the gamma-globin gene promoter after 48 h of treatment. At the post-transcriptional level, GTP treatment led to a drastic increase of the gamma-globin mRNA half-life. This stabilizing effect of GTP was mediated via the 3'-untranslated region (3'-UTR) of the gamma-globin mRNA. In conclusion, mechanism of GTP-mediated differentiation of K562 cells is linked to an early activation of gamma-globin gene transcription followed by a stabilization of its mRNA.
Morceau
F
F
Laboratoire de Recherche sur le Cancer et les Maladies du Sang, Centre Universitaire de Luxembourg, France.
Dupont
C
C
Palissot
V
V
Borde-Chiché
P
P
Trentesaux
C
C
Dicato
M
M
Diederich
M
M
D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D050981:Erythroid-Specific DNA-Binding Factors; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D050982:GATA1 Transcription Factor; D015972:Gene Expression Regulation, Neoplastic; D005914:Globins / Q000235:genetics / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D006160:Guanosine Triphosphate; D005914:Globins