Stem cell factor enhances erythropoietin-mediated transactivation of signal transducer and activator of transcription 5 (STAT5) via the PKA/CREB pathway

Boer, Arjen‐Kars; Drayer, A. Lyndsay; Vellenga, Edo

doi:10.1016/s0301-472x(03)00075-4

Cited by 17 publications

(19 citation statements)

References 44 publications

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“…Once phosphorylated, STAT5 is released from EpoR, homodimerizes in the cytosol, and translocates to the nucleus where it activates its target gene expression, including Bcl-X and cyclin D1 (53)(54)(55)(56)(57)(58). Phosphorylation of CREB by PKA enhances Epo-stimulated STAT5 transactivation by inducing recruitment of CREB/CBP/p300 to the STAT5 transactivational complex (58,59). Inactivation of Gpr48 caused dramatic decrease in the proliferation of definitive erythroid progenitors and erythroblast islands in fetal liver.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of G-protein-coupled Receptor 48 (Gpr48/Lgr4) Impairs Definitive Erythropoiesis at Midgestation through Down-regulation of the ATF4 Signaling Pathway

Song

Luo

et al. 2008

Journal of Biological Chemistry

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G-protein-coupled receptors (GPCRs), one of the most versatile groups of cell surface receptors, can recognize specific ligands from neural, hormonal, and paracrine organs and regulate cell growth, proliferation, and differentiation. Gpr48/LGR4 is a recently identified orphan GPCR with unknown functions. To reveal the functions of Gpr48 in vivo, we generated Gpr48 ؊/؊ mice and found that Gpr48 ؊/؊ fetuses displayed transient anemia during midgestation and abnormal definitive erythropoiesis. The dramatic decrease of definitive erythroid precursors (Ter119 pos population) in Gpr48 ؊/؊ fetal liver at E13.5 was confirmed by histological analysis and blood smear assays. Real-time PCR analyses showed that in Gpr48؊/؊ mice both adult hemoglobin ␣ and ␤ chains were decreased while embryonic hemoglobin chains (, ␤H1, and ⑀y) were increased, providing another evidence for the impairment of definitive erythropoiesis. Furthermore, proliferation was suppressed in Gpr48 ؊/؊ fetal liver with decreased c-Myc and cyclin D1 expression, whereas apoptosis was unaffected. ATF4, a key transcription factor in erythropoiesis, was downregulated in Gpr48 ؊/؊ fetal livers during midgestation stage through the cAMP-PKA-CREB pathway, suggesting that Gpr48 regulated definitive erythropoiesis through ATF4-mediated definitive erythropoiesis.Erythropoiesis occurs sequentially in distinct anatomical locations in two different phases during embryogenesis. The earlier phase is defined as primitive erythropoiesis, which, in the mouse, originates from the yolk sac at embryonic day 7.5 (E7.5), 3 and the later phase is definitive erythropoiesis, which was carried out in the fetal liver during midgestation after E12.5. Non-nucleated adult-type red blood cells are first generated in the fetal liver, the primary organ for erythropoiesis during midgestation from E12 to E16 (1). Erythropoiesis then transfers to bone marrow and spleen in the adult (2, 3). However, the molecular mechanism of regulating erythropoiesis has not been completely delineated. Most of the studies were focused on the transcription factors to explore the mechanisms of erythropoiesis (4, 5). In recent years, several transcription factors were also identified to regulate definitive erythropoiesis in fetal liver during midgestation (6 -11). One of the transcription factors is ATF4, which has been shown to regulate cell proliferation in response to a broad spectrum of cell stresses and can be either an activator or a repressor in response to different extracellular signals (12). ATF4 Ϫ/Ϫ mice have been reported to cause defective definitive erythropoiesis, and severe anemia at midgestation (13). Although receptors, such as c-Kit and EPOR, have been well studied in erythropoiesis (14), little is known on the function of G-proteincoupled receptors (GPCRs) in erythropoiesis during development (14, 15).The GPCR family represents the largest and most versatile group of cell surface receptors (16 -18). GPCRs can recognize their ligands, a diverse array of extracellular signals, then transmit th...

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Section: Discussionmentioning

confidence: 99%

Inactivation of G-protein-coupled Receptor 48 (Gpr48/Lgr4) Impairs Definitive Erythropoiesis at Midgestation through Down-regulation of the ATF4 Signaling Pathway

Song

Luo

et al. 2008

Journal of Biological Chemistry

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“…In addition, STAT5 has also been demonstrated to interact with cAMP-response element binding protein (CREB). STAT5 transcriptional activity was enhanced by the phosphorylation of CREB, which was induced by EPO and stem cell factor (Boer et al, 2002, Boer et al, 2003, Gewinner et al, 2004. CREB is a transcriptional factor whose downstream gene products, such as brain-derived neurotrophic factor (BDNF), have neuroprotective effects (Finkbeiner et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Signal transducers and activators of transcription 5 contributes to erythropoietin-mediated neuroprotection against hippocampal neuronal death after transient global cerebral ischemia

Zhang

Wang

Cao

et al. 2007

Neurobiology of Disease

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The signal transducers and activators of transcription (STAT) proteins are a group of transcriptional factors. Among them, STAT5 initiates a pro-survival signaling cascade. So far, little has been known about the role of STAT5 in cerebral ischemia and reperfusion. This study examines the phosphorylation status of STAT5 in hippocampal CA1 in the early stage after transient global cerebral ischemia in rats. Our data show that the phosphorylation of STAT5 was increased in hippocampal CA1 at 1 hour and 3 hours ischemia. Taking advantage of the neuroprotective effect of erythropoietin (EPO) in CA1, we further demonstrated that the administration of EPO enhanced the phosphorylation of STAT5, with SATA5a being phosphorylated earlier. The enhanced phosphorylation of STAT5 in the EPO-treated group was accompanied by the upregulation of STAT5 downstream gene products, Bcl-xL and XIAP. Consequently, ischemic CA1 neuronal damage was attenuated by the administration of EPO. Both the enhancement of STAT5 phosphorylation and the neuroprotection rendered by EPO were blocked by Tyrphostin, a selective inhibitor for Janus kinase 2, which is an upstream kinase of STAT5. These findings suggest an association between the activation of STAT5 and CA1 neuronal survival after cerebral ischemia.

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“…Cells were transfected by electroporation as previously described [25]. Cells were stimulated with TPO or SCF in the presence or absence of inhibitors (as indicated) for 6 hours and harvested.…”

Section: Transfection and Transactivation Assaysmentioning

confidence: 99%

“…Cell lysates were prepared as previously described [25], and sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting were performed according to standard procedures. Detection was performed according to manufacturer's guidelines (ECL, Amersham, Buckinghamshire, U.K.).…”

Section: Western Blottingmentioning

confidence: 99%

Stem Cell Factor Synergistically Enhances Thrombopoietin‐Induced STAT5 Signaling in Megakaryocyte Progenitors through JAK2 and Src Kinase

Drayer

Boer²,

Los³

et al. 2005

STEM CELLS

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Stem cell factor (SCF) has a potent synergistic effect during megakaryopoiesis when administered in combination with the major megakaryocytic cytokine, thrombopoietin (TPO). In this study we analyzed the underlying mechanisms with regard to STAT5 activity. TPO stimulation of MO7e cells resulted in STAT5 transactivation, which could be enhanced 1.6-fold by costimulation with SCF, whereas SCF alone did not induce STAT5 transcriptional activity. This costimulatory effect of SCF was reflected in an increase in TPO-induced STAT5 DNA binding and increased and prolonged STAT5 tyrosine phosphorylation in both MO7e cells and primary human megakaryocyte progenitors. In contrast, serine phosphorylation of STAT5 was constitutive and associated with an inhibitory effect on STAT5 transactivation. Signal transduction pathways that might synergize in TPO-mediated STAT5 transactivation were analyzed using specific pharmacological inhibitors and indicated an essential role for Janus-activated kinase 2 (JAK2) and a partial role for Src-family kinases. Costimulation with SCF was found to increase and prolong tyrosine phosphorylation of JAK2 and the TPO receptor c-mpl. In addition, the Src kinase inhibitor SU6656 partially downregulated the additional effect of SCF costimulation on STAT5 tyrosine phosphorylation. SCF-induced enhancement of JAK2 phosphorylation was not affected by inhibition of Src kinase, suggesting that both JAK2 and Src kinase mediate STAT5 tyrosine phosphorylation. Synergistic activation of JAK2 and Src kinase may thus contribute to the enhanced STAT5 signaling in the presence of TPO and SCF. Stem Cells 2005;23:240-251

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Stem cell factor enhances erythropoietin-mediated transactivation of signal transducer and activator of transcription 5 (STAT5) via the PKA/CREB pathway

Cited by 17 publications

References 44 publications

Inactivation of G-protein-coupled Receptor 48 (Gpr48/Lgr4) Impairs Definitive Erythropoiesis at Midgestation through Down-regulation of the ATF4 Signaling Pathway

Inactivation of G-protein-coupled Receptor 48 (Gpr48/Lgr4) Impairs Definitive Erythropoiesis at Midgestation through Down-regulation of the ATF4 Signaling Pathway

Signal transducers and activators of transcription 5 contributes to erythropoietin-mediated neuroprotection against hippocampal neuronal death after transient global cerebral ischemia

Stem Cell Factor Synergistically Enhances Thrombopoietin‐Induced STAT5 Signaling in Megakaryocyte Progenitors through JAK2 and Src Kinase

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