Serum and growth factors activate both the canonical extracellular signal-regulated kinase (ERK) 1/2 pathway and the ERK5/big mitogen-activated protein kinase 1 (BMK) 1 pathway. Pharmacological inhibition of the ERK1/2 pathway using PD98059 and U0126 prevents cyclin D1 expression and inhibits cell proliferation, arguing that the ERK1/2 pathway is rate limiting for cell-cycle re-entry. However, both PD98059 and U0126 also inhibit the ERK5/BMK1 pathway, raising the possibility that the anti-proliferative effect of such drugs may be due to inhibition of ERK5 or both pathways. Here we characterize the effect of the novel mitogen-activated protein kinase/ERK kinase (MEK) inhibitor, PD184352, on the ERK1/2 and ERK5 pathways in the Chinese hamster fibroblast cell line CCl39. In quiescent cells, serum-stimulated ERK1 activity was completely inhibited by PD184352 with an IC50 below 1μM, whereas ERK5 activation was unaffected even at 20μM. Serum-stimulated DNA synthesis and cyclin D1 expression was inhibited by low doses of PD184352, which abolished ERK1 activity but had no effect on ERK5. Similarly, in cycling cells PD184352 caused a dose-dependent G1 arrest and inhibition of cyclin D1 expression at low doses, which inhibited ERK1 but were without effect on ERK5. These results indicate that the anti-proliferative effect of PD184352 is due to inhibition of the classical ERK1/2 pathway and does not require inhibition of the ERK5 pathway.
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September 2002
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Research Article|
September 01 2002
Cell-cycle arrest by PD184352 requires inhibition of extracellular signal-regulated kinases (ERK) 1/2 but not ERK5/BMK1
Matthew S. SQUIRES;
Matthew S. SQUIRES
Signalling Programme, The Babraham Institute, Babraham Hall, Cambridge CB2 4AT, U.K.
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Paula M. NIXON;
Paula M. NIXON
Signalling Programme, The Babraham Institute, Babraham Hall, Cambridge CB2 4AT, U.K.
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Simon J. COOK
Simon J. COOK
1
Signalling Programme, The Babraham Institute, Babraham Hall, Cambridge CB2 4AT, U.K.
1To whom correspondence should be addressed (e-mail simon.cook@bbsrc.ac.uk).
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Publisher: Portland Press Ltd
Received:
March 05 2002
Revision Received:
May 01 2002
Accepted:
June 17 2002
Accepted Manuscript online:
June 17 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (2): 673–680.
Article history
Received:
March 05 2002
Revision Received:
May 01 2002
Accepted:
June 17 2002
Accepted Manuscript online:
June 17 2002
Citation
Matthew S. SQUIRES, Paula M. NIXON, Simon J. COOK; Cell-cycle arrest by PD184352 requires inhibition of extracellular signal-regulated kinases (ERK) 1/2 but not ERK5/BMK1. Biochem J 1 September 2002; 366 (2): 673–680. doi: https://doi.org/10.1042/bj20020372
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