Vascular smooth muscle cell polyploidization involves changes in chromosome passenger proteins and an endomitotic cell cycle.
Vascular smooth muscle cell polyploidization occurs during normal development and is enhanced under physiologic stress, but the mechanism of this cell cycle has not been explored. We show via time-lapse video imaging and immunofluorescence analyses that primary vascular smooth muscle cells (VSMC) undergo an endomitotic-type cell cycle, including a normal progression through part of mitosis. Mononuclear polyploid cells are generated by defects in sister chromatid separation and/or segregation, and cellular binucleation occurs by reversal of cytokinesis. To obtain further leads to regulators involved, we examined the chromosomal passenger proteins, Aurora B, inner centromere protein and Survivin, and concluded that Aurora B and inner centromere protein are normally colocalized in centromeres, the midzone, and the midbody during mitosis. Survivin, however, is dim and diffused; it does not colocalize with either Aurora B or inner centromere protein in VSMC, which could account for defects in sister chromatid separation and/or segregation and reversal of cytokinesis. In accordance with the reported dependency of Aurora B activity on Survivin, the Aurora B substrate, vimentin, is not phosphorylated during cytokinesis. Finally, the data show that ectopically expressed Survivin inhibits polyploidization in vascular smooth muscle cells. Hence, aberrant chromosome passenger protein activity and endomitosis are associated with VSMC polyploidization.
Nagata
Yuka
Y
Recognition and Formation, Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Japan.
Jones
Matthew R
MR
Nguyen
Hao G
HG
McCrann
Donald J
DJ
St Hilaire
Cynthia
C
Schreiber
Barbara M
BM
Hashimoto
Atsushi
A
Inagaki
Masaki
M
Earnshaw
William C
WC
Todokoro
Kazuo
K
Ravid
Katya
K
D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002467:Cell Nucleus / Q000378:metabolism; D002503:Centromere / Q000737:chemistry / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis / Q000378:metabolism*; D020090:Chromosome Segregation / Q000502:physiology; D048749:Cytokinesis / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009363:Neoplasm Proteins; D010766:Phosphorylation; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077022:Survivin; D014746:Vimentin / Q000378:metabolism
C107489:BIRC5 protein, human; D002868:Chromosomal Proteins, Non-Histone; C083767:INCENP protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D014746:Vimentin; C576921:AURKB protein, human; C576925:Aurkb protein, rat; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases