Regulation of vascular smooth muscle cell proliferation by plasma membrane Ca(2+)-ATPase.
We have previously shown that reductions in c-Myb-dependent transcription inhibit cell cycle progression and decrease intracellular Ca2+ concentrations in vascular smooth muscle cells (VSMC). We now report that these effects are largely mediated by a 4- to 10-fold increased rate of La(3+)-sensitive 45Ca extrusion, which is associated with 2- to 4-fold increased levels of plasma membrane Ca(2+)-ATPase 1 (PMCA1) mRNA and protein. PMCA4 mRNA, present at much lower concentrations, undergoes similar changes during suppression of c-Myb activity. We also report that PMCA1 expression is regulated during VSMC cell cycle progression, such that levels of PMCA1 are 40% lower at the G1/S interface than at G0. Moreover, transient overexpression of PMCA1a in VSMC elevates the 45Ca efflux rate by approximately 2-fold, decreases resting and peak thapsigargin-releasable Ca2+ concentrations at G1/S by 43% (68 nM) and 52% (160 nM), respectively, and reduces the rate of cell proliferation by over 2.5-fold. These data define a mechanism for c-Myb-dependent Ca2+ homeostasis and support a critical role for PMCA in the regulation of VSMC growth.
Husain
M
M
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.
Jiang
L
L
See
V
V
Bein
K
K
Simons
M
M
Alper
S L
SL
Rosenberg
R D
RD
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis* / Q000378:metabolism; D027682:Cation Transport Proteins; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000201:enzymology*; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006706:Homeostasis; D007527:Isoenzymes / Q000096:biosynthesis; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology*; D053499:Plasma Membrane Calcium-Transporting ATPases; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection
D027682:Cation Transport Proteins; D018398:Homeodomain Proteins; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C106185:engrailed homeobox proteins; D019284:Thapsigargin; D053499:Plasma Membrane Calcium-Transporting ATPases; C506955:Atp2b1 protein, rat; D000252:Calcium-Transporting ATPases; D002118:Calcium