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* Center for Human Genetics, Boston University School of Medicine,
Boston, MA 02118; and Communicated by Yuet Wai Kan, University of California, San
Francisco, CA, December 18, 2000 (received for review June 26, 2000)
Despite considerable concerns with pharmacological stimulation of
fetal hemoglobin (Hb F) as a therapeutic option for the
Medical Sciences
Mechanism for fetal globin gene expression: Role of the soluble
guanylate cyclase-cGMP-dependent protein
kinase pathway
,
, and
Department of Medicine, Maggiore
Hospital Istituto Ricerca Cura Carattere Scientifico, University of
Milan, Milan 20122, Italy
-globin
disorders, the molecular basis of action of Hb F-inducing agents
remains unclear. Here we show that an intracellular pathway including
soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase (PKG)
plays a role in induced expression of the 
-globin gene. sGC, an
obligate heterodimer of 
- and -subunits, participates in a
variety of physiological processes by converting GTP to cGMP. Northern
blot analyses with erythroid cell lines expressing different -like
globin genes showed that, whereas the -subunit is expressed at
similar levels, high-level expression of the -subunit is
preferentially observed in erythroid cells expressing -globin but
not those expressing -globin. Also, the levels of expression of the
-globin gene correlate to those of the -subunit. sGC activators
or cGMP analogs increased expression of the -globin gene in
erythroleukemic cells as well as in primary erythroblasts from normal
subjects and patients with -thalassemia. Nuclear run-off assays
showed that the sGC activator protoporphyrin IX stimulates
transcription of the -globin gene. Furthermore, increased expression
of the -globin gene by well known Hb F-inducers such as hemin and
butyrate was abolished by inhibiting sGC or PKG activity. Taken
together, these results strongly suggest that the sGC-PKG pathway
constitutes a mechanism that regulates expression of the -globin
gene. Further characterization of this pathway should permit us to
develop new therapeutics for the -globin disorders.
To whom reprint requests should be addressed at: Center
for Human Genetics, Boston University School of Medicine, 700 Albany Street, W-408, Boston, MA 02118-2394. E-mail: tikuta{at}bu.edu.
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