Downregulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in vascular smooth muscle cells by p27(KIP1), an inhibitor of neointima formation in the rat carotid artery.

Chen, D; Krasinski, Kevin; Sylvester, Andrew; Chen, J; Nisen, Perry D.; Andrés, Vicente

doi:10.1172/jci119414

Cited by 179 publications

(147 citation statements)

References 70 publications

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“…p27 kip1 reportedly abrogates the activities of both CDK2 and CDK4 as well as VSMC proliferation in vitro and in vivo after ballooninjury in pig (Tanner et al, 2000). Some drugs that upregulate p27 kip1 expression reportedly exhibit potent anti-proliferative activities on VSMCs (Chen et al, 1997;Marra et al, 2000). Thus, our fi nding that OD78 selectively upregulates p27 kip1 expression is consistent with its greater inhibitory effects on the expression of multiple cell cycle proteins.…”

Section: Figsupporting

confidence: 72%

Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27^kip1in Rat Aortic Vascular Smooth Muscle Cells

Tudev¹,

Lim²,

Park³

et al. 2011

Biomolecules and Therapeutics

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(PDGF)-BB is a potent growth factor produced by platelets, VSMCs, and endothelial cells in the injured vascular wall (Majesky et al., 1990;Miyauchi et al., 1998). PDGF initiates the activation of intracellular signal transduction pathways that contribute to VSMC proliferation, migration, and collagen Atherosclerosis and post-angiography restenosis are associated with intimal thickening and concomitant vascular smooth muscle cell (VSMC) proliferation. Obovatol, a major biphenolic component isolated from the Magnolia obovata leaf, is known to have antiinfl ammatory and anti-tumor activities. The goal of the present study was to enhance the inhibitory effects of obovatol to improve its potential as a preventive or therapeutic agent in atherosclerosis and restenosis. Platelet-derived growth factor (PDGF)-BB-induced proliferation of rat aortic smooth muscle cells (RASMCs) was examined in the presence or absence of a newly synthesized obovatol derivative, OD78. The observed anti-proliferative effect of OD78 was further investigated by cell counting and [ 3 H]-thymidine incorporation assays. Treatment with 1-4 μM OD78 dose-dependently inhibited the proliferation and DNA synthesis of 25 ng/ ml PDGF-BB-stimulated RASMCs. Accordingly, OD78 blocked PDGF-BB-induced progression from the G 0 /G 1 to S phase of the cell cycle in synchronized cells. OD78 decreased the expression levels of CDK4, cyclin E, and cyclin D1 proteins, as well as the phosphorylation of retinoblastoma protein and proliferating cell nuclear antigen; however, it did not change the CDK2 expression level. In addition, OD78 inhibited downregulation of the cyclin-dependent kinase inhibitor (CKI) p27 kip1 . However, OD78 did not affect the CKI p21 cip1 or phosphorylation of early PDGF signaling pathway. These results suggest that OD78 may inhibit PDGF-BBinduced RASMC proliferation by perturbing cell cycle progression, potentially through p27 kip1 pathway activation. Consequently, OD78 may be developed as a potential anti-proliferative agent for the treatment of atherosclerosis and angioplasty restenosis. (Ammon and Wahl, 1991). PDGF-BB propagates mitogenic signals through the autophosphorylation of its respective PDGF beta-receptor (Rβ) on tyrosine residues, thus triggering downstream signal transduction and cell cycle progression (Blenis, 1993;Heldin et al., 1998;Ahn et al., 1999).Cell cycle phases are coordinated by the expression and activation of regulatory proteins, including complexes of cyclins and cyclin-dependent kinases (CDK) (Braun-Dullaeus et al., 1998). The kinase activity of these CDK-cyclin complexes is further negatively regulated by two classes of cyclin-dependent kinase inhibitors (CKIs) (Sherr and Roberts, 1999). INK4 family members (p16 INK4a and p15 INK4b ) inhibit only CDK4 and CDK6 (Ortega et al., 2002), while cip family members (p21 cip1

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Section: Figsupporting

confidence: 72%

Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27^kip1in Rat Aortic Vascular Smooth Muscle Cells

Tudev¹,

Lim²,

Park³

et al. 2011

Biomolecules and Therapeutics

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“…It has been shown that transduction of cells with a gene encoding for a nonphosphorylatable, constitutively active form of the pRb gene product significantly inhibited neointimal hyperplasia (167). Overexpression of cell cycle inhibitors, such as p21 and p27 by an adenoviral technology or p53 by a naked plasmid vector, significantly reduced neointimal hyperplasia in several animal models (168)(169)(170)(171)(172). In addition, increased expression of the homeobox gene GAX reduced the vasculoproliferative response after arterial wall injury in both rat and rabbit models (173)(174)(175).…”

Section: Gene Therapy Approachmentioning

confidence: 99%

The cell cycle: A critical therapeutic target to prevent vascular proliferative disease

Charron

Nili

Strauss

2006

Canadian Journal of Cardiology

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“…Cyclic AMP did not affect p27 KIP1 and p21 CIP1 in primary astrocytes or in C.LT.T.1.1 cells, whereas cyclic AMP promotes an increase in p27 KIP1 in macrophages (Kato et al, 1994), in vascular smooth muscle cells (Chen et al, 1997), and in oligodendrocytes (Friessen et al, 1997). In contrast, cyclic AMP inhibits the expression of p27 KIP1 in Swiss 3T3 cells (Mann et al, 1997).…”

Section: Effects Of Cyclic Amp On Cyclins and Cdks In Astrocytesmentioning

confidence: 88%

Effects of Cyclic AMP on Components of the Cell Cycle Machinery Regulating DNA Synthesis in Cultured Astrocytes

Gagelin

Toru-Delbauffe²,

Gavaret³

et al. 1999

Journal of Neurochemistry

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Cyclic AMP is a second messenger for various hormones that inhibits cell multiplication and DNA synthesis in cultured astrocytes. We examined the effects of increasing intracellular cyclic AMP on the catalytic (cdks) and regulatory (cyclins and ckis) components of cyclindependent protein kinases, which regulate progression of the cell cycle before completion of DNA synthesis, in primary cultured astrocytes and in an astrocytic cell line C.LT.T.1.1. The amount of cdk4 changed little during the cell cycle and was not affected by cyclic AMP. There was little cdk1 and cdk2 in quiescent cells, and their expression increased during the G 1 -S phases. Cyclic AMP strongly inhibited cdk1 and cdk2 expression. Transforming growth factor ␤ also inhibited cdk1 expression in primary astrocytes. Cyclic AMP did not affect the two ckis p27 KIP1 and p21 CIP1 . There was little cyclin D1 in quiescent cells, but it increased during the G 1 phase and was reduced by cyclic AMP. Cyclin E increased during the G 1 -S phases and was not affected by cyclic AMP in primary astrocytes. The amount of cyclin A was low in quiescent cells and increased during the G 1 -S phases. Expression of its mRNA and protein was inhibited by cyclic AMP. The protein kinase activities associated with complexes of cyclins and cdks were increased by growth factors and prevented by cyclic AMP. We conclude that cyclic AMP inhibits progression of the cell cycle in astrocytes at least by preventing the expression of the regulatory subunits, cyclins D1 and A, and catalytic subunits, cdk1 and cdk2, of cyclin-regulated protein kinases.

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Downregulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in vascular smooth muscle cells by p27(KIP1), an inhibitor of neointima formation in the rat carotid artery.

Cited by 179 publications

References 70 publications

Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27^kip1in Rat Aortic Vascular Smooth Muscle Cells

Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27^kip1in Rat Aortic Vascular Smooth Muscle Cells

The cell cycle: A critical therapeutic target to prevent vascular proliferative disease

Effects of Cyclic AMP on Components of the Cell Cycle Machinery Regulating DNA Synthesis in Cultured Astrocytes

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Downregulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in vascular smooth muscle cells by p27(KIP1), an inhibitor of neointima formation in the rat carotid artery.

Cited by 179 publications

References 70 publications

Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27kip1in Rat Aortic Vascular Smooth Muscle Cells

Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27kip1in Rat Aortic Vascular Smooth Muscle Cells

The cell cycle: A critical therapeutic target to prevent vascular proliferative disease

Effects of Cyclic AMP on Components of the Cell Cycle Machinery Regulating DNA Synthesis in Cultured Astrocytes

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Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27^kip1in Rat Aortic Vascular Smooth Muscle Cells

Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27^kip1in Rat Aortic Vascular Smooth Muscle Cells