p38 MAP kinase activation mediates γ-globin gene induction in erythroid progenitors

Pace, Betty S.; Qian, Xin; Sangerman, Jose; Ofori-Acquah, Solomon F.; Baliga, B S; Han, Jiahuai; Critz, Stuart D.

doi:10.1016/s0301-472x(03)00235-2

Cited by 79 publications

(69 citation statements)

References 38 publications

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“…17,20,26 The direct role of p38 in mediating g-globin gene induction in erythroid progenitors has been demonstrated by expression of MAPK kinase kinase 3 (MKK3) and MKK6, the immediate upstream activators of p38. 37 The contribution of p38 to pyrimidine starvationinduced differentiation is supported by evidence that pyridinylimidazole p38 inhibitors prevented K562 cell differentiation. However, since some of the pyridinylimidazole p38 inhibitors also prevent nucleoside transport, 34,35 it was essential to distinguish the effects of these compounds on p38, from those on CPEC uptake.…”

Section: Discussionmentioning

confidence: 96%

CPEC induces erythroid differentiation of human myeloid leukemia K562 cells through CTP depletion and p38 MAP kinase

et al. 2004

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Cyclopentenyl cytosine (CPEC) is a carbocyclic cytidine analog inhibitor of CTP synthetase and experimental drug for combination chemotherapy. CPEC treatment (50 nM) depleted intracellular CTP and induced a specific S-phase arrest and erythroid differentiation of human erythroleukemia K562 cells. The equilibrative nucleoside transporters (ENT1, 2) facilitated uptake of CPEC into K562 cells as evidenced by both NBMPR and dipyridamole inhibition of CPEC-mediated CTP depletion and erythroid differentiation. Incubation with the pyridinylimidazole p38 MAPK inhibitors, SB203580 or SB220025, suppressed both the CPEC-induced cell cycle arrest and differentiation of K562 cells. SB203580 also prevented the cell cycle arrest and erythroid differentiation of K562 cells induced by Leflunomide (LEF), a non-nucleoside inhibitor of the de novo pyrimidine pathway, without affecting LEF-induced depletion of pyrimidine pools. Finally, selective knockdown of p38 MAPK by using Smart Poolt siRNA to p38 MAPK significantly decreased the CPEC-induced differentiation of K562 cells. These results suggest that endogenous activity of p38 MAP kinases may be required for committing K562 cells to cell cycle arrest and erythroid differentiation under conditions of CTP depletion.

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Section: Discussionmentioning

confidence: 96%

CPEC induces erythroid differentiation of human myeloid leukemia K562 cells through CTP depletion and p38 MAP kinase

et al. 2004

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“…In a previous study from our laboratory, butyrate was also shown to increased HbF production in patients with SCD by increasing the efficiency of translation of γ-globin mRNA. 34 Butyrate was also shown to activate signaling through the soluble guanylate cyclase 35 and p38 MAP kinase 36 pathways. It is not yet clear how these signaling activities lead to the transcriptional activation of the γ-globin genes.…”

Section: Mechanisms Of Pharmacologicalmentioning

confidence: 99%

Induction of Fetal Hemoglobin in the Treatment of Sickle Cell Disease

Fathallah

Atweh

2006

Hematology

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Reactivation of fetal hemoglobin (HbF) expression is an important therapeutic option in patients with hemoglobin disorders. In sickle cell disease (SCD), an increase in HbF inhibits the polymerization of sickle hemoglobin and the resulting pathophysiology. Hydroxyurea, an inducer of HbF, has already been approved for the treatment of patients with moderate and/or severe SCD. Recent clinical trials with other pharmacological inducers of HbF, such as butyrate and decitabine, have shown considerable promise. In this chapter, we highlight the important clinical trials with pharmacological inducers of HbF, discuss their mechanisms of action and speculate about the future of this therapeutic approach in the treatment of patients with SCD.

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“…Interestingly, signal transduction cascades involved in growth and cellular stress response may modify globin gene regulation. In experimental models, activation of mitogen-activated protein (MAP) kinase 11 and cyclic nucleotide pathways (cyclic guanosine monophosphate 12,13 and cyclic adenosine monophosphate) 14 modulate globin gene expression to some degree. Cytokines provide a means to coordinate several cascades and cause robust augmentation of ␥-globin mRNA and HbF expression ex vivo.…”

Section: Introductionmentioning

confidence: 99%

Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming

Sripichai

Kiefer

Bhanu

et al. 2009

Blood

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Therapeutic regulation of globin genes is a primary goal of translational research aimed toward hemoglobinopathies. Signal transduction was used to identify chromatin modifications and transcription factor expression patterns that are associated with globin gene regulation. Histone modification and transcriptome profiling were performed using adult primary CD34 ؉ cells cultured with cytokine combinations that produced low versus high levels of gamma-globin mRNA and fetal hemoglobin (HbF). Embryonic, fetal,

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p38 MAP kinase activation mediates γ-globin gene induction in erythroid progenitors

Cited by 79 publications

References 38 publications

CPEC induces erythroid differentiation of human myeloid leukemia K562 cells through CTP depletion and p38 MAP kinase

CPEC induces erythroid differentiation of human myeloid leukemia K562 cells through CTP depletion and p38 MAP kinase

Induction of Fetal Hemoglobin in the Treatment of Sickle Cell Disease

Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming

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