Phorbol Ester Inhibits the Phosphorylation of the Retinoblastoma Protein without Suppressing Cyclin D-associated Kinase in Vascular Smooth Muscle Cells

Sasaguri, Toshiyuki; Ishida, Akio; Kosaka, Chiya; Nishimura, Hiroshi; Ogata, Jun

doi:10.1074/jbc.271.14.8345

Cited by 69 publications

(30 citation statements)

References 54 publications

(62 reference statements)

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“…Although a number of CDKs phosphorylate pRb, the suppression of CDK2 alone may be sufficient to prevent pRb hyperphosphorylation (53,54). In addition, several reports suggest that inhibition of CDK4 may not be necessary for cell cycle progression arrest (55,56). Therefore, inhibition of CDK2, cyclin E, and cyclin D1 expression and of pRb phosphorylation may be sufficient for cell cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

Genistein Inhibits Rat Aortic Smooth Muscle Cell Proliferation Through the Induction of p27kip1

Lee

Lim

et al. 2008

J Pharmacol Sci

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Abstract. Diet is one of the most important factors that influence the risks for cardiovascular diseases. Genistein, an isoflavone found in soy, may benefit the cardiovascular system. Here, we investigated the effect of genistein on platelet-derived growth factor (PDGF)-BB-induced proliferation of primary cultured rat aortic smooth muscle cells (RASMCs). Genistein significantly inhibited 25 ng / ml PDGF-BB-induced RASMC proliferation and [ 3 H]-thymidine incorporation into DNA at 10, 20, and 40 μM. In accordance with these findings, genistein blocked the PDGF-BB-inducible progression through G 0 / G 1 to S phase of the cell cycle in synchronized cells. Western blot analysis showed that genistein not only inhibited phosphorylation of retinoblastoma protein (pRb) and expression of cyclin E, cyclin-dependent kinase (CDK) 2, and proliferating cell nuclear antigen (PCNA) protein, but also inhibited downregulation of cyclin-dependent kinase inhibitor (CKI) p27 kip1 . However, genistein did not affect p21 cip1 , CDK4, and cyclin D1 expression or early signal transduction through PDGF beta-receptor, extracellular signal-regulated kinases 1 / 2 (ERK1 /2), Akt, and phospholipase C (PLC) γ1 phosphorylation. These results suggest that genistein inhibits PDGF-BB-induced RASMC proliferation via G 0 /G 1 arrest in association with induction of p27 kip1 , which may contribute to the beneficial effects of genistein on the cardiovascular system.

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Section: Discussionmentioning

confidence: 99%

Genistein Inhibits Rat Aortic Smooth Muscle Cell Proliferation Through the Induction of p27kip1

Lee

Lim

et al. 2008

J Pharmacol Sci

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“…The majority of studies point towards cyclins E and A as targets for PKC regulation during the GUS transition. PMA treatment of vascular smooth muscle cells inhibits the phosphorylation of the retinoblastoma protein without suppression of the cyclin-D-associated kinase [93]. The inhibition of Cdk2 activity in these cells correlated with reduced expression of cyclins E and A 1931.…”

Section: Lessons From Yeast Cellsmentioning

confidence: 94%

“…As described above, PKC inhibits late G1 events, such as cyclin E and A expression, Cdk2 activation, and Rb phosphorylation, but not early GI events such as cyclin D expression and Cdk4 activation [13,93,1021. Suppressed expression of cyclin D1 was reported only in PMA-treated PKCE-overexpressing Rat6 fibroblasts, without any detectable effect on Rb phosphorylation [103].…”

Section: Lessons From Yeast Cellsmentioning

confidence: 99%

Linking Protein Kinase C to Cell‐Cycle Control

Livneh

Fishman

1997

European Journal of Biochemistry

198

114

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Protein kinase C (PKC) isoenzymes are involved in diverse cellular functions, including differentiation, growth control, tumor promotion, and cell death. In recent years, evidence has began to emerge suggesting a role for PKC in cell cycle control. A paper published recently, demonstrating a functional link between PKC and cell cycle control in yeast (Marini, N. J., Meldrum, E., Buehrer, B., Hubberstey, A. V., Stone, D. E., Traynor-Kaplan, A. & Reed, S. I. (1996) EMBO J. 15, 3040-3052), strengthens this data. Thus, the existence of cell-cycle-regulated pathways involving PKC in both yeast and mammals indicate that PKC may be a conserved regulator of cell cycle events that links signal transduction pathways and the cell-cycle machinery. In this paper, we will review current data on the cell cycle components that are targets for PKC regulation.PKC enzymes appear to operate as regulators of the cell cycle at two sites, during G1 progression and G 2 M transition. In G1, the overall effect of PKC activation is inhibition of the cell cycle at mid to late G1. This cell cycle inhibition correlates with a blockage in the normal phosphorylation of the tumor suppressor retinoblastoma Rb protein, presumably through an indirect mechanism. The reduced activity of the cyclin-dependent kinase, Cdk2, appears to be the major effect of PKC activation in various cell systems. This may also underlie the inhibition of Rb phosphorylation exhibited by PKC activation. Several mechanisms were described in different studieq on the regulation of Cdk2 activity by PKC; reduced Cdk-activating kinase activity, diminished expression of the Cdk2 partners cyclins E or A, and the increased expression of the cyclin-dependent inhibitors, p2lWAF1 and p27K'P', which are capable of binding to cyclidCdk2 complexes.PKC enzymes were also shown to play a role in G2/M transition. Among the suggested mechanisms is suppression of Cdc2 activity. However, most of the published data strongly implicate PKC in lamin B phosphorylation and nuclear envelope disassembly.Keywords: protein kinase C ; cell cycle; cyclin ; cyclin-dependent kinase; Cdk inhibitor; retinoblastoma protein; p53 protein; phorbol ester; GUS transition; G2/M transition. Protein kinase C and growth regulationThe term protein kinase C (PKC) stands for a group of at least ten serinehhreonine kinases that are characterized by a high degree of similarity in their catalytic kinase domains and cysteine-rich regions [l-41. The PKC family is subdivided into three groups; the classical PKC members (a, p, y) are Ca2+ and diacylglycerol-dependent, the novel PKCs (6, E , q and d) are Ca2+-independent but diacylglycerol-dependent and the atypical PKCs ([ and 2) are not activated by Ca*+ and diacylglycerol in vitro [3, 41. This may account for the multiplicity and diversity of the cellular activities implicated to be mediated by PKC, sinceCorrespondence to

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“…Several CDKs are known to phosphorylate pRb (Akiyama et al, 1992;Connell-Crowley et al, 1998). The inhibition of CDK4, cyclins D1 and E, and Rb protein phosphorylation may be suffi cient, and inhibition of CDK2 may not be necessary, to arrest cell cycle progression (Sasaguri et al, 1996;Brooks et al, 1997). The expression of PCNA, a phospho-Rb-mediated gene product in the early G0/G1 and S phases of the cell cycle, was also inhibited by OD78.…”

Section: Discussionmentioning

confidence: 99%

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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Phorbol Ester Inhibits the Phosphorylation of the Retinoblastoma Protein without Suppressing Cyclin D-associated Kinase in Vascular Smooth Muscle Cells

Cited by 69 publications

References 54 publications

Genistein Inhibits Rat Aortic Smooth Muscle Cell Proliferation Through the Induction of p27kip1

Genistein Inhibits Rat Aortic Smooth Muscle Cell Proliferation Through the Induction of p27kip1

Linking Protein Kinase C to Cell‐Cycle Control

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

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Phorbol Ester Inhibits the Phosphorylation of the Retinoblastoma Protein without Suppressing Cyclin D-associated Kinase in Vascular Smooth Muscle Cells

Cited by 69 publications

References 54 publications

Genistein Inhibits Rat Aortic Smooth Muscle Cell Proliferation Through the Induction of p27kip1

Genistein Inhibits Rat Aortic Smooth Muscle Cell Proliferation Through the Induction of p27kip1

Linking Protein Kinase C to Cell‐Cycle Control

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

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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