Downregulation of cyclin-dependent kinase inhibitor; p57(kip2), is involved in the cell cycle progression of vascular smooth muscle cells.
Immature vascular smooth muscle cells (VSMCs) proliferate responding to extrinsic mitogens and accumulate in neointima after arterial injuries. Cell proliferation is positively regulated by cyclin/cyclin-dependent kinase (CDK) complex and negatively controlled by CDK inhibitors; CKIs such as p27(kip1) and p57(kip2). In this study, embryonic rat thoracic aorta VSMCs; A10 were G0/G1 arrested by serum starvation, re-stimulated with serum, and harvested every four hours. Both CKIs co-expressed in quiescent VSMCs and rapidly diminished by stimulation. Protein level of p27(kip1) was regulated by both transcription and post-transcription, but that of p57(kip2) was mainly by post-transcription. Supplemental overexpression of p57(kip2) inhibited the activations of G1 cyclin/CDKs and subsequent hyperphosphorylations of all three retinoblastoma pocket proteins as well as G1/S transition of cell cycle. Our findings suggest that the downregulations of not only p27(kip1), but also p57(kip2) responding to mitogenic stimulation, play key roles in the cell cycle progression of VSMCs.
Nakano
Noritsugu
N
Department of Cardiovascular Medicine, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan. norida@med.hokudai.ac.jp
Urasawa
Kazushi
K
Takagi
Yasushi
Y
Saito
Takahiko
T
Kaneta
Satoshi
S
Ishikawa
Susumu
S
Higashi
Hideaki
H
Tsutsui
Hiroyuki
H
Hatakeyama
Masanori
M
Kitabatake
Akira
A
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002478:Cells, Cultured; D056746:Cyclin G; D056766:Cyclin G1; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D044967:Serum
C534704:Ccng1 protein, rat; D056746:Cyclin G; D056766:Cyclin G1; D050761:Cyclin-Dependent Kinase Inhibitor p57; D016213:Cyclins; D012333:RNA, Messenger