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 βmajor-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.
Skip Nav Destination
Article navigation
November 2010
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
October 25 2010
Antagonistic roles of the ERK and p38 MAPK signalling pathways in globin expression, haem biosynthesis and iron uptake1
Louay Mardini;
Louay Mardini
*Lady Davis Institute for Medical Research, McGill University, 3755 Côte Sainte-Catherine Road, Montreal, Quebec, Canada, H3T 1E2
Search for other works by this author on:
Jadwiga Gasiorek;
Jadwiga Gasiorek
*Lady Davis Institute for Medical Research, McGill University, 3755 Côte Sainte-Catherine Road, Montreal, Quebec, Canada, H3T 1E2
Search for other works by this author on:
Anna Derjuga;
Anna Derjuga
*Lady Davis Institute for Medical Research, McGill University, 3755 Côte Sainte-Catherine Road, Montreal, Quebec, Canada, H3T 1E2
Search for other works by this author on:
Lucie Carrière;
Lucie Carrière
*Lady Davis Institute for Medical Research, McGill University, 3755 Côte Sainte-Catherine Road, Montreal, Quebec, Canada, H3T 1E2
Search for other works by this author on:
Matthias Schranzhofer;
Matthias Schranzhofer
*Lady Davis Institute for Medical Research, McGill University, 3755 Côte Sainte-Catherine Road, Montreal, Quebec, Canada, H3T 1E2
Search for other works by this author on:
Barry H. Paw;
Barry H. Paw
†Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, One Blackfan Circle, Boston, MA 02115, U.S.A.
Search for other works by this author on:
Prem Ponka;
Prem Ponka
*Lady Davis Institute for Medical Research, McGill University, 3755 Côte Sainte-Catherine Road, Montreal, Quebec, Canada, H3T 1E2
‡Department of Medicine & Department of Physiology, McGill University, 3755 Côte Sainte-Catherine Road, Montreal, Quebec, Canada, H3T 1E2
Search for other works by this author on:
Volker Blank
Volker Blank
2
*Lady Davis Institute for Medical Research, McGill University, 3755 Côte Sainte-Catherine Road, Montreal, Quebec, Canada, H3T 1E2
‡Department of Medicine & Department of Physiology, McGill University, 3755 Côte Sainte-Catherine Road, Montreal, Quebec, Canada, H3T 1E2
2To whom correspondence should be addressed (email volker.blank@mcgill.ca).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
April 08 2010
Revision Received:
August 23 2010
Accepted:
August 26 2010
Accepted Manuscript online:
August 26 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 432 (1): 145–151.
Article history
Received:
April 08 2010
Revision Received:
August 23 2010
Accepted:
August 26 2010
Accepted Manuscript online:
August 26 2010
Citation
Louay Mardini, Jadwiga Gasiorek, Anna Derjuga, Lucie Carrière, Matthias Schranzhofer, Barry H. Paw, Prem Ponka, Volker Blank; Antagonistic roles of the ERK and p38 MAPK signalling pathways in globin expression, haem biosynthesis and iron uptake1. Biochem J 15 November 2010; 432 (1): 145–151. doi: https://doi.org/10.1042/BJ20100541
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.