Antagonistic roles of the ERK and p38 MAPK signalling pathways in globin expression, haem biosynthesis and iron uptake1

Abstract

Late-stage erythroid cells synthesize large quantities of haemoglobin, a process requiring the co-ordinated regulation of globin and haem synthesis as well as iron uptake. In the present study, we investigated the role of the ERK (extracellular-signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) signalling pathways in MEL (mouse erythroleukaemia) cell differentiation. We found that treatment of HMBA (hexamethylene bisacetamide)-induced MEL cells with the ERK pathway inhibitor UO126 results in an increase in intracellular haem and haemoglobin levels. The transcript levels of the genes coding for β(major)-globin, the haem biosynthesis enzyme 5-aminolevulinate synthase 2 and the mitochondrial iron transporter mitoferrin 1 are up-regulated. We also showed enhanced expression of globin and transferrin receptor 1 proteins upon UO126 treatment. With respect to iron uptake, we found that ERK inhibitor treatment led to an increase in both haem-bound and total iron. In contrast, treatment of MEL cells with the p38 MAPK pathway inhibitor SB202190 had the opposite effect, resulting in decreased globin expression, haem synthesis and iron uptake. Reporter assays showed that globin promoter and HS2 enhancer-mediated transcription was under the control of MAPKs, as inhibition of the ERK and p38 MAPK pathways led to increased and decreased gene activity respectively. Our present results suggest that the ERK1/2 and p38α/β MAPKs play antagonistic roles in HMBA-induced globin gene expression and erythroid differentiation. These results provide a novel link between MAPK signalling and the regulation of haem biosynthesis and iron uptake in erythroid cells.

Cellular Iron Depletion Stimulates the JNK and p38 MAPK Signaling Transduction Pathways, Dissociation of ASK1-Thioredoxin, and Activation of ASK1

“…Considering this study, it is of interest to note that blocking the p38 pathway using the inhibitor, SB202190, resulted in reduced total iron uptake in erythroid cells, highlighting the potential significance of this pathway in affecting iron metabolism (63). Indeed, the alterations in p38 phosphorylation observed in this study after manipulation of cellular iron status indicate that this signaling pathway has potential roles in regulating molecules involved in iron metabolism.…”

NLRP3 promotes autophagy of urate crystals phagocytized by human osteoblasts

“…Our results suggest that phagocytic stimulation by MSU required ERK activation but not p38, which seems to act as a repressor of MSU phagocytosis by OBs. Such antagonistic roles of ERK1/2 and p38 MAPK are reminiscent of another condition in which ERK1/2 and p38 MAPK differentially regulate heme biosynthesis [88]. …”

Expression of (Pro)renin Receptor During Rapamycin-Induced Erythropoiesis in K562 Erythroleukemia Cells and Its Possible Dual Actions on Erythropoiesis

“…Binding of prorenin/renin to (P)RR stimulates the intracellular signaling including ERK1/2 (Liu et al 2011;Nguyen 2011). Mardini et al (2010) showed that the ERK pathway inhibitor U0126 increased intracellular heme and hemoglobin levels, as well as ALAS2 mRNA expression levels, in Friendvirus-infected MEL (mouse erythroleukemia) cells. The ERK1/2 activation by the (P)RR-mediated signaling may be silenced by (P)RR-specific siRNA, resulting in elevated expression levels of ALAS2 mRNA in the present study.…”