PMID- 20738258
OWN - NLM
STAT- MEDLINE
DCOM- 20101206
LR  - 20211020
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 432
IP  - 1
DP  - 2010 Nov 15
TI  - Antagonistic roles of the ERK and p38 MAPK signalling pathways in globin 
      expression, haem biosynthesis and iron uptake.
PG  - 145-51
LID - 10.1042/BJ20100541 [doi]
AB  - 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 
      beta(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 p38alpha/beta 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.
FAU - Mardini, Louay
AU  - Mardini L
AD  - Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, 
      Canada.
FAU - Gasiorek, Jadwiga
AU  - Gasiorek J
FAU - Derjuga, Anna
AU  - Derjuga A
FAU - Carriere, Lucie
AU  - Carriere L
FAU - Schranzhofer, Matthias
AU  - Schranzhofer M
FAU - Paw, Barry H
AU  - Paw BH
FAU - Ponka, Prem
AU  - Ponka P
FAU - Blank, Volker
AU  - Blank V
LA  - eng
GR  - P01 HL032262/HL/NHLBI NIH HHS/United States
GR  - R01 DK070838/DK/NIDDK NIH HHS/United States
GR  - MOP-79361/CAPMC/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Acetamides)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Butadienes)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hemoglobins)
RN  - 0 (Imidazoles)
RN  - 0 (Nitriles)
RN  - 0 (Pyridines)
RN  - 0 (U 0126)
RN  - 42VZT0U6YR (Heme)
RN  - 9004-22-2 (Globins)
RN  - E1UOL152H7 (Iron)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - LA133J59VU (hexamethylene bisacetamide)
RN  - PVX798P8GI (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole)
SB  - IM
MH  - Acetamides/pharmacology
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Blotting, Northern
MH  - Butadienes/pharmacology
MH  - Cell Differentiation/drug effects
MH  - Cell Line, Tumor
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Expression/drug effects
MH  - Globins/genetics/*metabolism
MH  - Heme/*biosynthesis
MH  - Hemoglobins/metabolism
MH  - Imidazoles/pharmacology
MH  - Immunoblotting
MH  - Iron/*pharmacokinetics
MH  - MAP Kinase Signaling System/drug effects/*physiology
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 1/antagonists & inhibitors/metabolism
MH  - Mitogen-Activated Protein Kinase 3/antagonists & inhibitors/metabolism
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Nitriles/pharmacology
MH  - Pyridines/pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism
EDAT- 2010/08/27 06:00
MHDA- 2010/12/14 06:00
CRDT- 2010/08/27 06:00
PHST- 2010/08/27 06:00 [entrez]
PHST- 2010/08/27 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
AID - BJ20100541 [pii]
AID - 10.1042/BJ20100541 [doi]
PST - ppublish
SO  - Biochem J. 2010 Nov 15;432(1):145-51. doi: 10.1042/BJ20100541.