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Selective inhibition of MEK1/2 reveals a differential requirement for ERK1/2 signalling in the regulation of HIF-1 in response to hypoxia and IGF-1

Oncogene volume 26, pages 3920–3929 (2007)Cite this article

Abstract

The transcription factor hypoxia-inducible factor 1 (HIF-1) plays a pivotal role in tumour growth and progression, and HIF-1 is regulated through a number of signalling pathways. Here, we investigated the involvement of the mitogen-activated protein kinase (MAPK) signalling pathway in HIF-1 regulation. We found that overexpression of wild-type (WT) extracellular signal regulated protein kinase 1 (ERK1) greatly potentiated HIF-1 activation in hypoxia and HIF-1α induced in response to insulin growth-like factor 1 (IGF-1). Conversely, treatment of tumour cells with the MEK1/2 inhibitors PD98059 or U0216, or expression of a dominant-negative form of ERK1 blocked HIF-1 activation in hypoxia without affecting HIF-1α induction, localization or binding of HIF-1β. Interestingly however, the highly selective MEK1/2 inhibitor PD184352 did not inhibit HIF-1 activity or vascular endothelial growth factor (VEGF) induced in response to hypoxia but blocked HIF-1α protein and HIF-1 activity induced by IGF-1 stimulation without affecting HIF-1α mRNA levels. Finally, we found that ERK5 phosphorylation status was not significantly affected by hypoxia in the presence or absence of PD184352. Taken together, our data suggest that although ERK1/2 signalling is important for HIF-1α induction and HIF-1 activity in response to IGF-1, it is dispensable for the induction of HIF-1α and activation of HIF-1 in response to hypoxia.

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Acknowledgements

We thank Professor Paul Workman and Dr Veronica Carroll for critical review of the manuscript. We thank Professors Richard Marais and Caroline Springer (The Institute of Cancer Research, UK) for helpful discussions and input. We also thank Julia Bárdos and all other members of the Ashcroft lab for their input and support. This work was funded by The Institute of Cancer Research and Cancer Research UK (CUK) Programme Grant Number C309/A2187.

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Authors and Affiliations

  1. Cell Growth Regulation and Angiogenesis Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK

    K M Sutton, N-M Chau, A Ahmed, N Perusinghe, J Yang & M Ashcroft

  2. MAP Kinase Group, Laboratory of Molecular Signalling, Signalling Programme, The Babraham Institute, Cambridge, UK

    S Hayat & S Cook

  3. Institute of Signalling, Developmental Biology and Cancer Research, Nice, France

    J Pouyssegur & R Le Floch

  4. Microscopy Facility, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK

    N Perusinghe

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  1. K M Sutton
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Correspondence to M Ashcroft.

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Sutton, K., Hayat, S., Chau, NM. et al. Selective inhibition of MEK1/2 reveals a differential requirement for ERK1/2 signalling in the regulation of HIF-1 in response to hypoxia and IGF-1. Oncogene 26, 3920–3929 (2007). https://doi.org/10.1038/sj.onc.1210168

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