title: GTP-mediated differentiation of the human K562 cell line: transient overexpression of GATA-1 and stabilization of the gamma-globin mRNA.
abstract: 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.
authors.affiliation: Laboratoire de Recherche sur le Cancer et les Maladies du Sang, Centre Universitaire de Luxembourg, France.
authors.forename: F
authors.initials: F
authors.lastname: Morceau
authors.forename: C
authors.initials: C
authors.lastname: Dupont
authors.forename: V
authors.initials: V
authors.lastname: Palissot
authors.forename: P
authors.initials: P
authors.lastname: Borde-Chiché
authors.forename: C
authors.initials: C
authors.lastname: Trentesaux
authors.forename: M
authors.initials: M
authors.lastname: Dicato
authors.forename: M
authors.initials: M
authors.lastname: Diederich
mesh_terms: 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
chemical_list: 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