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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Ausenda, S. Cappellini, M. D. Ikuta, T. |
| Description | Author Affiliation: Ikuta T ( Center for Human Genetics, Boston University School of Medicine, Boston, MA 02118, USA. tikuta@bu.edu); |
| Abstract | Despite considerable concerns with pharmacological stimulation of fetal hemoglobin (Hb F) as a therapeutic option for the beta-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 gamma-globin gene. sGC, an obligate heterodimer of alpha- and beta-subunits, participates in a variety of physiological processes by converting GTP to cGMP. Northern blot analyses with erythroid cell lines expressing different beta-like globin genes showed that, whereas the beta-subunit is expressed at similar levels, high-level expression of the alpha-subunit is preferentially observed in erythroid cells expressing gamma-globin but not those expressing beta-globin. Also, the levels of expression of the gamma-globin gene correlate to those of the alpha-subunit. sGC activators or cGMP analogs increased expression of the gamma-globin gene in erythroleukemic cells as well as in primary erythroblasts from normal subjects and patients with beta-thalassemia. Nuclear run-off assays showed that the sGC activator protoporphyrin IX stimulates transcription of the gamma-globin gene. Furthermore, increased expression of the gamma-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 gamma-globin gene. Further characterization of this pathway should permit us to develop new therapeutics for the beta-globin disorders. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 4 |
| Volume Number | 98 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2001-02-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cyclic GMP-Dependent Protein Kinases Physiology Cyclic GMP Metabolism Gene Expression Globins Genetics Guanylate Cyclase Signal Transduction Butyrates Pharmacology Drug Effects Hemin K562 Cells Leukemia, Erythroblastic, Acute Solubility Tumor Cells, Cultured Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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