Affiliation:
1. Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Division of Cell and Molecular Biology, Toronto General Hospital Research Institute, and Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5G-2C4
Abstract
Calcineurin mediates repression of plasma membrane Ca2+-ATPase-4 (PMCA4) expression in neurons, whereas c-Myb is known to repress PMCA1 expression in vascular smooth muscle cells (VSMC). Here, we describe a novel mouse VSMC line (MOVAS) in which45Ca efflux rates decreased 50%, fura 2-AM-based intracellular Ca2+concentrations ([Ca2+]i) increased twofold, and real-time RT-PCR and Western blot revealed a ∼40% decrease in PMCA4 expression levels from G0to G1/S in the cell cycle, where PMCA4 constituted ∼20% of total PMCA protein. Although calcineurin activity increased fivefold as MOVAS progressed from G0to G1/S, inhibition of this increase with either BAPTA or retroviral transduction with peptide inhibitors of calcineurin (CAIN), or its downstream target nuclear factor of activated T cells (NFAT) (VIVIT), had no effect on the repression of PMCA4 mRNA expression at G1/S. By contrast, Ca2+-independent activity of the calmodulin-dependent protein kinase-II (CaMK-II) increased eightfold as MOVAS progressed from G0to G1/S, and treatment with an inhibitor of CaMK-II (KN-93) or transduction of a c-Myb-neutralizing antibody significantly alleviated the G1/S-associated repression of PMCA4. These data show that G1/S-specific PMCA4 repression in proliferating VSMC is brought about by c-Myb and CaMK-II and that calcineurin may regulate cell cycle-associated [Ca2+]ithrough alternate targets.
Publisher
American Physiological Society
Cited by
49 articles.
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