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 γ-globin gene is a realistic approach to therapy of β-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 α- and γ-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 γ-globin gene promoter was transiently increased. Moreover, GTP moderately stimulated the γ-globin gene promoter after 48 h of treatment. At the post-transcriptional level, GTP treatment led to a drastic increase of the γ-globin mRNA half-life. This stabilizing effect of GTP was mediated via the 3'-untranslated region (3'-UTR) of the γ-globin mRNA. In conclusion, mechanism of GTP-mediated differentiation of K562 cells is linked to an early activation of γ-globin gene transcription followed by a stabilization of its mRNA.
- Erythroid differentiation
- MRNA stability