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The role of ERk5 in cell cycle arrest differentiation and senescence.

Reference	BB/C509190/1
Principal Investigator / Supervisor	Dr Simon Cook
Co-Investigators / Co-Supervisors	Dr Shaista Hayat
Institution	Babraham Institute
Department	Babraham Institute Department
Funding type	Research
Value (£)	211,540
Status	Completed
Type	Research Grant
Start date	16/09/2004
End date	15/03/2008
Duration	42 months

Abstract

The classical Ras-regulated Raf-MEK-ERK1/2 cascade regulates cell cycle re-entry, being able to promote cell proliferation or cell cycle arrest depending on the duration and magnitude of ERK1/2 activation. The parallel MEK5-ERK5 pathway may also be regulated by Ras but to date it has predominantly been implicated in promoting cell proliferation. In preliminary studies we have found that both constitutively active mutants MEK1E and MEK5D can promote a G1 cell cycle arrest when expressed in HEK293 cells. Furthermore, whilst MEK5D fails to elicit neurite outgrowth in PC12 cells (a paradigm for cell cycle arrest and differentiation) it seems that both MEK1E and MEK5D can cause a cessation of proliferation in these cells. Based on these preliminary studies we propose to investigate the role of the MEK5-ERK5 pathway in cell cycle arrest in three model systems. We will define how activation of ERK5 by MEK5D promotes a G1 cell cycle arrest in HEK293 cells and will investigate the role of ERK5 in Ras-induced senescence in E6/E7 expressing Human Ovarian Surface Epithelial (HOSE) cells which harbour a Dox-inducible RasV12 construct. We will study the role of ERK5 in NGF- and Ras-dependent cell cycle arrest and differentiation in PC12 cells. Finally we will use inducible expression or activation systems to selectively activate the ERK5 pathway and analyse ERK5-inducible transcripts using affymetrix gene chip technology. The results of this study should define the role of ERK5 in cell cycle arrest, differentiation and senescence in model systems and for the first time identify a partial ERK5 transcriptome related to ERK5-dependent cell cycle arrest. This information, which will be freely available by a web link, should help to inform and focus future research efforts seeking to define the cellular targets of the ERK5 pathway.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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