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

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Author(s): Dedman Alexandra | Majeed Yasser | Tumova Sarka | Zeng Fanning | Kumar Bhaskar | Munsch Christopher | Bateson Alan | Wittmann Jürgen | Jäck Hans-Martin | Porter Karen | Beech David

Journal: BMC Molecular Biology
ISSN 1471-2199

Volume: 12;
Issue: 1;
Start page: 30;
Date: 2011;
Original page

Keywords: alternative splicing | nonsense-mediated decay | cationic channel | transient receptor potential canonical 1

ABSTRACT
Abstract Background 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. Results 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. Conclusions 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.
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