TRPC1 transcript variants, inefficient nonsense-mediated decay and low up-frameshift-1 in vascular smooth muscle cells

Springer Science and Business Media LLC - Tập 12 - Trang 1-10 - 2011
Alexandra M Dedman1,2, Yasser Majeed1,2, Sarka Tumova1,2, Fanning Zeng1,2, Bhaskar Kumar1,2, Christopher Munsch3, Alan N Bateson2, Jürgen Wittmann4, Hans-Martin Jäck4, Karen E Porter1,5, David J Beech1,2
1Multidisciplinary Cardiovascular Research Centre, UK
2Institute of Membrane & Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
3Yorkshire Heart Centre, General Infirmary at Leeds, Leeds, UK
4Division of Molecular Immunology, Nikolaus Fiebiger-Center for Molecular Medicine, University of Erlangen-Nürnberg, Erlangen, Germany
5Faculty of Medicine & Health, University of Leeds, Leeds, UK

Tóm tắt

Transient Receptor Potential Canonical 1 (TRPC1) is a widely-expressed mammalian cationic channel with functional effects that include stimulation of cardiovascular remodelling. The initial aim of this study was to investigate variation in TRPC1-encoding gene transcripts. Extensive TRPC1 transcript alternative splicing was observed, with exons 2, 3 and 5-9 frequently omitted, leading to variants containing premature termination codons. Consistent with the predicted sensitivity of such variants to nonsense-mediated decay (NMD) the variants were increased by cycloheximide. However it was notable that control of the variants by NMD was prominent in human embryonic kidney 293 cells but not human vascular smooth muscle cells. The cellular difference was attributed in part to a critical protein in NMD, up-frameshift-1 (UPF1), which was found to have low abundance in the vascular cells. Rescue of UPF1 by expression of exogenous UPF1 was found to suppress vascular smooth muscle cell proliferation. The data suggest: (i) extensive NMD-sensitive transcripts of TRPC1; (ii) inefficient clearance of aberrant transcripts and enhanced proliferation of vascular smooth muscle cells in part because of low UPF1 expression.

Tài liệu tham khảo

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