Authors: Bailey, Lakiea¹; Kuroyanagi, Yuichi¹; Franco-Penteado, Carla F.²; Conran, Nicola²; Costa, Fernando F.²; Ausenda, Sabrina³; Cappellini, Maria D.³; Ikuta, Tohru¹

Source: British Journal of Haematology, Volume 138, Number 3, August 2007 , pp. 382-395(14)

Publisher: Wiley-Blackwell

Abstract:

Summary

The present study found that the cyclic adenosine monophosphate (cAMP)-dependent pathway efficiently induced γ-globin expression in adult erythroblasts, and this pathway plays a role in γ-globin gene (HBG) expression in β-thalassaemia. Expression of HBG mRNA increased to about 46% of non-HBA mRNA in adult erythroblasts treated with forskolin, while a cyclic guanosine monophosphate (cGMP) analogue induced HBG mRNA to levels <20% of non-HBA mRNA. In patients with β-thalassaemia intermedia, cAMP levels were elevated in both red blood cells and nucleated erythroblasts but no consistent elevation was found with cGMP levels. The transcription factor cAMP response element binding protein (CREB) was phosphorylated in nucleated erythroblasts and its phosphorylation levels correlated with HBG mRNA levels of the patients. Other signalling molecules, such as mitogen-activated protein kinases and signal transducers and activators of transcription proteins, were phosphorylated at variable levels and showed no correlations with the HBG mRNA levels. Plasma levels of cytokines, such as erythropoietin, stem cell factor and transforming growth factor-β were increased in patients, and these cytokines induced both HBG mRNA expression and CREB phosphorylation. These results demonstrate that the cAMP-dependent pathway, the activity of which is augmented by multiple cytokines, plays a role in regulating HBG expression in β-thalassaemia.

Keywords: β-thalassaemia; γ-globin; cyclic adenosine monophosphate; signal transduction; intracellular pathways

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2141.2007.06673.x

Affiliations: 1: Department of Medicine, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA, USA 2: Haematology and Haemotherapy Centre, University of Campinas, Campinas, SP, Brazil, 3: Hereditary Anaemia Centre, Maggiore Hospital IRCCS, University of Milan, Milan, Italy

Publication date: 2007-08-01

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