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  • Original Paper
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Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression

Oncogene volume 22, pages 2633–2642 (2003)Cite this article

Abstract

Accumulating evidence suggests that angiotensin II type II (AT2) receptor subtype negatively regulates cell proliferation in pathophysiological conditions associated with tissue remodeling. However, the mechanisms through which AT2 receptor achieves this effect remain poorly understood. In this study, we demonstrate that expression of AT2 receptor inhibits the proliferation of rat fibroblasts in a ligand-independent manner. The antiproliferative action of AT2 is dependent on the density of surface receptors. We show that AT2 receptor expression negatively regulates G1 phase progression in both cycling cells and G0-arrested cells stimulated to re-enter the cell cycle, but has no detectable effect on apoptosis. The delay in cell-cycle progression of AT2-expressing cells is associated with downregulation of cyclin E expression, decreased assembly of cyclin E-Cdk2 complexes, and the resulting attenuation of Cdk2 activation. The induction of Cdk4 expression and activity is also markedly attenuated, which likely contributes to the inhibition of cyclin E expression. Ectopic expression of Cdk4 alleviates the proliferation defect of AT2-expressing cells. These findings suggest that the growth-inhibitory effects of the AT2 receptor are attributable in part to its spontaneous inhibitory action on the cell cycle machinery.

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Acknowledgements

We thank E Harlow for Cdk4-HA plasmid, M Servant for discussions, and N Tessier for assistance with the FACS analysis. This work was supported by a grant from the Canadian Institutes for Health Research (CIHR; FRN-14168) and by a Medical School grant from Merck Frosst Canada. G Rodier and P Coulombe are recipients of a fellowship and studentship from the National Cancer Institute of Canada and CIHR, respectively. S Meloche is an Investigator of the CIHR.

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  1. Bruno Gingras and Geneviève Rodier: These two authors contributed equally to the work and are listed alphabetically.

Authors and Affiliations

  1. Institut de recherches cliniques de Montréal and Departments of Pharmacology and Molecular Biology, Université de Montréal, 110 Pine Avenue West, Montreal, H2W 1R7, Quebec, Canada

    Bruno Gingras, Geneviève Rodier, Edith Giasson, Philippe Coulombe & Sylvain Meloche

  2. INSERM U127, Institut Fédératif de Recherche Circulation Paris VII, Hôpital Lariboisière, Université Denis Diderot, Paris, France

    Catherine Chassagne

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  1. Bruno Gingras
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Correspondence to Sylvain Meloche.

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Gingras, B., Rodier, G., Giasson, E. et al. Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression. Oncogene 22, 2633–2642 (2003). https://doi.org/10.1038/sj.onc.1206346

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