Expression of the γ-globin gene is sustained by the cAMP-dependent pathway in β-thalassaemia

Lakiea Bailey, Yuichi Kuroyanagi, Carla F. Franco-Penteado, Nicola Conran, Fernando F. Costa, Sabrina Ausenda, Maria D. Cappellini, Tohru Ikuta

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)382-395
Number of pages14
JournalBritish Journal of Haematology
Volume138
Issue number3
DOIs
StatePublished - Aug 1 2007

Fingerprint

Thalassemia
Globins
Cyclic AMP
Erythroblasts
Gene Expression
Messenger RNA
Cyclic GMP
Cytokines
Phosphorylation
STAT Transcription Factors
Cyclic AMP Response Element-Binding Protein
Stem Cell Factor
beta-Thalassemia
Response Elements
Transforming Growth Factors
Colforsin
Erythropoietin
Mitogen-Activated Protein Kinases
Carrier Proteins
Transcription Factors

Keywords

  • Cyclic adenosine monophosphate
  • Intracellular pathways
  • Signal transduction
  • β-thalassaemia
  • γ-globin

ASJC Scopus subject areas

  • Hematology

Cite this

Expression of the γ-globin gene is sustained by the cAMP-dependent pathway in β-thalassaemia. / Bailey, Lakiea; Kuroyanagi, Yuichi; Franco-Penteado, Carla F.; Conran, Nicola; Costa, Fernando F.; Ausenda, Sabrina; Cappellini, Maria D.; Ikuta, Tohru.

In: British Journal of Haematology, Vol. 138, No. 3, 01.08.2007, p. 382-395.

Research output: Contribution to journalArticle

Bailey, L, Kuroyanagi, Y, Franco-Penteado, CF, Conran, N, Costa, FF, Ausenda, S, Cappellini, MD & Ikuta, T 2007, 'Expression of the γ-globin gene is sustained by the cAMP-dependent pathway in β-thalassaemia', British Journal of Haematology, vol. 138, no. 3, pp. 382-395. https://doi.org/10.1111/j.1365-2141.2007.06673.x
Bailey, Lakiea ; Kuroyanagi, Yuichi ; Franco-Penteado, Carla F. ; Conran, Nicola ; Costa, Fernando F. ; Ausenda, Sabrina ; Cappellini, Maria D. ; Ikuta, Tohru. / Expression of the γ-globin gene is sustained by the cAMP-dependent pathway in β-thalassaemia. In: British Journal of Haematology. 2007 ; Vol. 138, No. 3. pp. 382-395.
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