Differential Effects of the Cyclin-Dependent Kinase Inhibitors p27
 Kip1
 , p21
 Cip1
 , and p16
 Ink4
 on Vascular Smooth Muscle Cell Proliferation

Tanner, Felix C.; Boehm, Manfred; Akyürek, Levent M.; San, Hong; Yang, Zhi Yong; Tashiro, J.; Nabel, Gary J.; Nabel, Elizabeth G.

doi:10.1161/01.cir.101.17.2022

Cited by 220 publications

(189 citation statements)

References 14 publications

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“…Indeed, the cyclin-CDK complex plays a critical role in cell cycle regulation by controlling phase transition of cell cycle progression, in which cyclin is the regulatory unit and CDK is the catalytic component of the complex. 26,27 The present results revealed that the PPARδ agonist leads to increased ROS production at 15 and 120 min as compared with controls. Thus, we investigated the effects of ROS sensitive signals such as PKC, cPLA 2 and p38 MAPK.…”

Section: Discussionsupporting

confidence: 55%

PPARδ agonist-mediated ROS stimulates mouse embryonic stem cell proliferation through cooperation of p38 MAPK and Wnt/β-catenin

Jeong

Lee²,

Lee³

et al. 2009

Cell Cycle

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N O T D I S T R I B U T E .PPARδ (peroxisome proliferator-activated receptor delta) is a member of the nuclear receptor superfamily. However, its function in tissues and cells is unknown, particularly as related to stem cell biology. We therefore investigated the PPARδ effects on DNA synthesis in mouse embryonic stem cells (ES cells) and its related signal pathways. PPARδ increased biphasic reactive oxygen species (ROS) production at 15 min and at 120 min incubation. PPARδ significantly increased [ 3 H] thymidine incorporation levels at various concentrations (10 -8 M to 10 -6 M) and incubation times (12 to 48 hr), and this activity was blocked by antioxidants. In addition, PPARδ increased protein kinase C (PKC), cytosolic phospholipase A 2 (cPLA 2 ) and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, and Wnt/β-catenin activation. PPARδ increased the protein levels of cell cycle regulators, and these levels were abolished by antioxidants, bisindolymaleimide I, SB203580 and β-catenin specific siRNA. In addition, the effect of PPARδ on increased [ 3 H] thymidine incorporation was blocked by bisindolymaleimide I, SB203580 and β-catenin specific siRNA. In conclusion, PPARδ agonist enhanced mouse ES cells proliferation through ROS-mediated p38 MAPK and Wnt/β-catenin activation.

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Section: Discussionsupporting

confidence: 55%

PPARδ agonist-mediated ROS stimulates mouse embryonic stem cell proliferation through cooperation of p38 MAPK and Wnt/β-catenin

Jeong

Lee²,

Lee³

et al. 2009

Cell Cycle

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“…Consistent with the view that CDKIs are major negative regulators of the cell cycle, overexpression of Cip/Kip family members (p21 Cip1 , p27 Kip1 ) blocks the G 1 exit in VSMC and other cell types (5,6). Data emerging from recent studies, however, suggest that CDKIs p21…”

mentioning

confidence: 58%

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Mitogenic Induction of p21Cip1 by Modulating the Protein Kinase Cδ Pathway in Vascular Smooth Muscle Cells

Wakino¹,

Kintscher²,

Liu³

et al. 2001

Journal of Biological Chemistry

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The cyclin-dependent kinase inhibitor p21Cip1 is upregulated in response to mitogenic stimulation in various cells. PPAR␥ ligands troglitazone (TRO, 10 M) and rosiglitazone (RSG, 10 M) attenuated the induction of p21Cip1 protein by platelet-derived growth factor (PDGF) and insulin without affecting cognate mRNA levels in rat aortic smooth muscle cells (RASMC). The protein kinase C␦ (PKC␦) inhibitor rottlerin also blocked the induction of p21Cip1 protein, whereas the conventional PKC isotype inhibitor Gö 6976 had no effect. Kinetic studies using the protein synthesis inhibitor cycloheximide showed that TRO, RSG, and rottlerin shortened the half-life of p21 Cip1 expression in PDGFtreated RASMC. PPAR␥ ligands enhanced proteintyrosine-phosphatase activity in RASMC, which may be the mechanism for decreased PKC␦ tyrosine phosphorylation and activity. PPAR␥ ligands regulate p21Cip1 at a post-translational level by blocking PKC␦ signaling and accelerating p21Cip1 turnover.Vascular smooth muscle cells (VSMC) 1 in the normal vessel wall proliferate at a very low frequency. Injury to the endothelium results in the release of mitogens that stimulate quiescent, G 0 /G 1 -arrested VSMC to reenter the cell cycle, replicate DNA, and divide. VSMC hyperplasia is a key event in the formation of restenotic and atherosclerotic lesions in the vasculature (1, 2). Cyclin-dependent kinases (CDKs) are serinethreonine protein kinases that regulate cell cycle progression after forming complexes with and being activated by cyclins (3). Mitogenic activation of cyclin D⅐CDK4, cyclin D⅐CDK6, and cyclin E⅐CDK2 during the G 1 phase results in phosphorylation of retinoblastoma gene (Rb) proteins. In its hyperphosphorylated state, Rb functions as a gatekeeper for the G 1 3 S transition by binding and sequestering E2F, a transcription factor that induces the expression of a battery of genes that encode the enzymatic machinery for S phase DNA synthesis. Cyclindependent kinase inhibitors (CDKIs) can negatively regulate the mitogen-induced cascade of G 1 events by inhibiting CDK activity and preventing Rb phosphorylation (3, 4).Consistent with the view that CDKIs are major negative regulators of the cell cycle, overexpression of Cip/Kip family members (p21 Cip1 , p27 Kip1 ) blocks the G 1 exit in VSMC and other cell types (5, 6). Data emerging from recent studies, however, suggest that CDKIs p21Cip1 and p27 Kip1 can also function as positive regulators during the G 1 phase as assembly factors to promote formation of cyclin⅐CDK holoenzyme complexes (3, 7). Such a role for CDKIs may explicate apparent paradoxical observations that p21Cip1 is frequently up-regulated after mitogenic stimulation of quiescent cells (8,9). In rat VSMC cell lines, prevention of mitogen-induced p21 Cip1 expression by antisense oligodeoxynucleotides attenuated both DNA synthesis and cell proliferation (10). We recently reported that ligands for the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR␥) inhibited Rb phosphorylation and G 1 3 S transition in ra...

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“…These findings provide an important mechanistic link between the induction of NOR1-dependent Skp2 expression in response to mitogenic signaling and downstream p27 protein abundance. Maintaining elevated p27 levels prevents neointima formation following vascular injury (10). Conversely, recent work by Wu et al (24) has outlined that Skp2 deficiency increases p27 protein levels and inhibits VSMC proliferation.…”

Section: Discussionmentioning

confidence: 97%

“…The rate-limiting component of this SCF complex is Skp2 (S phase kinase-associated protein 2) (7), which is induced by growth factors and responsible for substrate recognition and degradation of p27 (8,9). In vascular cells, overexpression of p27 inhibits neointima formation, whereas its deficiency accelerates atherosclerosis formation (10,11). Conversely, ectopic SKP2 expression decreases p27 levels in VSMC, induces VSMC proliferation, and promotes pathological neointima formation (12,13).…”

Section: Vascular Smooth Muscle Cells (Vsmc)mentioning

confidence: 99%

Transcriptional Regulation of S Phase Kinase-associated Protein 2 by NR4A Orphan Nuclear Receptor NOR1 in Vascular Smooth Muscle Cells

Gizard

Zhao

Findeisen

et al. 2011

Journal of Biological Chemistry

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Background:The nuclear receptor NOR1 serves a mitogenic role; however, the mechanisms underlying this activity remain poorly understood. Results: NOR1 induces Skp2 transcription, leading to a decrease in p27 protein abundance. Conclusion: Skp2 constitutes a NOR1-regulated gene, which contributes to the mitogenic activity of this nuclear receptor. Significance: These studies detail a novel transcriptional cascade regulating proliferation.

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Differential Effects of the Cyclin-Dependent Kinase Inhibitors p27 ^Kip1 , p21 ^Cip1 , and p16 ^Ink4 on Vascular Smooth Muscle Cell Proliferation

Cited by 220 publications

References 14 publications

PPARδ agonist-mediated ROS stimulates mouse embryonic stem cell proliferation through cooperation of p38 MAPK and Wnt/β-catenin

PPARδ agonist-mediated ROS stimulates mouse embryonic stem cell proliferation through cooperation of p38 MAPK and Wnt/β-catenin

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Mitogenic Induction of p21Cip1 by Modulating the Protein Kinase Cδ Pathway in Vascular Smooth Muscle Cells

Transcriptional Regulation of S Phase Kinase-associated Protein 2 by NR4A Orphan Nuclear Receptor NOR1 in Vascular Smooth Muscle Cells

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Differential Effects of the Cyclin-Dependent Kinase Inhibitors p27 Kip1 , p21 Cip1 , and p16 Ink4 on Vascular Smooth Muscle Cell Proliferation

Cited by 220 publications

References 14 publications

PPARδ agonist-mediated ROS stimulates mouse embryonic stem cell proliferation through cooperation of p38 MAPK and Wnt/β-catenin

PPARδ agonist-mediated ROS stimulates mouse embryonic stem cell proliferation through cooperation of p38 MAPK and Wnt/β-catenin

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Mitogenic Induction of p21Cip1 by Modulating the Protein Kinase Cδ Pathway in Vascular Smooth Muscle Cells

Transcriptional Regulation of S Phase Kinase-associated Protein 2 by NR4A Orphan Nuclear Receptor NOR1 in Vascular Smooth Muscle Cells

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Differential Effects of the Cyclin-Dependent Kinase Inhibitors p27 ^Kip1 , p21 ^Cip1 , and p16 ^Ink4 on Vascular Smooth Muscle Cell Proliferation