The S100A6 calcium-binding protein regulates endothelial cell-cycle progression and senescence

Authors

  • Leyuan Bao,

    1. Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, LIGHT Laboratories, University of Leeds, UK
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  • Adam F. Odell,

    1. Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, LIGHT Laboratories, University of Leeds, UK
    2. Molecular Epidemiology Unit, Faculty of Medicine & Health, LIGHT Laboratories, University of Leeds, UK
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  • Sam L. Stephen,

    1. Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, LIGHT Laboratories, University of Leeds, UK
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  • Stephen B. Wheatcroft,

    1. Diabetes & Cardiovascular Research, Faculty of Medicine & Health, LIGHT Laboratories, University of Leeds, UK
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  • John H. Walker,

    1. Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, LIGHT Laboratories, University of Leeds, UK
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  • Sreenivasan Ponnambalam

    Corresponding author
    • Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, LIGHT Laboratories, University of Leeds, UK
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Correspondence

S. Ponnambalam, Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, LIGHT Laboratories, University of Leeds, Clarendon Way, Leeds LS2 9JT, UK

Fax: +44 113 343 7738

Tel: +44 113 343 3007

E-mail: s.ponnambalam@leeds.ac.uk

Abstract

Endothelial cells regulate many aspects of vascular physiology, including vasculogenesis and angiogenesis. The S100 family of calcium-binding proteins regulates many aspects of cell function but their roles in vascular physiology are less well understood. Herein, we investigated the expression and function of S100-related family members in endothelial cells. Analysis of total endothelial mRNAs using a human gene chip array revealed significant gene expression of the S100 calcium-binding protein family members S100A6, S100A10, S100A11 and S100A13. We then examined the expression and functional properties of the major S100 family member, S100A6, in vascular endothelial cells. Comparison of primary and transformed human cells revealed significant differences in S100A6 protein levels in these cells. In primary human endothelial cells, S100A6 was present in both the nucleus and the cytoplasm. To assess the function of endothelial S100A6, we depleted protein levels using RNA interference and this caused increased cell-cycle arrest in the G2/M phase under different conditions. S100A6 depletion caused a decrease in both cyclin-dependent kinase 1 (CDK1) and phospho-CDK1 levels, which are essential for eukaryote cell-cycle progression. S100A6 depletion also decreased expression of CDK1, cyclin A1 (CCNA1) and cyclin B (CCNB1) genes with effects on cell-cycle progression. Depletion of endothelial S100A6 levels also elevated β-galactosidase expression, which is an important hallmark of cellular senescence and exit from the mammalian cell cycle. We thus propose that S100A6 has an important role in regulating endothelial commitment to, and progression through, the cell cycle.

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