TY - JOUR
T1 - Expression of the γ-globin gene is sustained by the cAMP-dependent pathway in β-thalassaemia
AU - Bailey, Lakiea
AU - Kuroyanagi, Yuichi
AU - Franco-Penteado, Carla F.
AU - Conran, Nicola
AU - Costa, Fernando F.
AU - Ausenda, Sabrina
AU - Cappellini, Maria D.
AU - Ikuta, Tohru
PY - 2007/8
Y1 - 2007/8
N2 - 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.
AB - 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.
KW - Cyclic adenosine monophosphate
KW - Intracellular pathways
KW - Signal transduction
KW - β-thalassaemia
KW - γ-globin
UR - http://www.scopus.com/inward/record.url?scp=34447120236&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34447120236&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2141.2007.06673.x
DO - 10.1111/j.1365-2141.2007.06673.x
M3 - Article
C2 - 17614826
AN - SCOPUS:34447120236
SN - 0007-1048
VL - 138
SP - 382
EP - 395
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 3
ER -