Dominant Negative c-Jun Inhibits Platelet-Derived Growth Factor-Directed Migration by Vascular Smooth Muscle Cells

Ioroi, Takeshi; Yamamori, Motohiro; Yagi, Kazuichi; Hirai, Midori; Zhan, Yumei; Kim, Shokei; Itoh, Hiroshi

doi:10.1254/jphs.91.145

Cited by 23 publications

(15 citation statements)

References 16 publications

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“…The effects of platonin on c-Jun phosphorylation and p27 expression in PDGF-BB-stimulated VSMCs Several lines of evidence indicate that the JNK-mediated phosphorylation of c-Jun is necessary for cell proliferation [20,21] . Zhan et al [22] also reported that the pivotal role of c-Jun in PDGF-BB-induced VSMC proliferation is mediated by the down-regulation of p27 expression, an inhibitor of cyclindependent kinase (CDK).…”

Section: Resultsmentioning

confidence: 99%

“…Activated JNKs result in the phosphorylation of many transcription factors, including the c-Jun component of the activator protein (AP)-1 transcription family [26,27] . c-Jun is known to be required for PDGF-induced VSMC migration and proliferation, and JNK knockdown can attenuate cell migration and proliferation in PDGF-stimulated VSMCs [20,22] . Furthermore, dominant-negative c-Jun lacking the transactivation domain of wild-type c-Jun (Ad-DN-cJun), which specifically blocks AP-1 transcriptional activity, significantly inhibited PDGF-BB-induced VSMC proliferation and suppressed PDGF-BB-induced down-regulation of CDK p27 [21] .…”

Section: Discussionmentioning

confidence: 99%

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Platonin inhibited PDGF-BB-induced proliferation of rat vascular smooth muscle cells via JNK1/2-dependent signaling

Chang

Uen²,

Chen

et al. 2011

Acta Pharmacol Sin

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Aim: To examine the inhibitory actions of the immunoregulator platonin against proliferation of rat vascular smooth muscle cells (VSMCs). Methods: VSMCs were prepared from the thoracic aortas of male Wistar rats. Cell proliferation was examined using MTT assays. Cell cycles were analyzed using flow cytometry. c-Jun N-terminal kinase (JNK)1/2, extracellular signal-regulated kinase (ERK)1/2, AKT, and c-Jun phosphorylation or p27 expression were detected using immunoblotting. Results: Pretreatment with platonin (1-5 μmol/L) significantly suppressed VSMC proliferation stimulated by PDGF-BB (10 ng/mL) or 10% fetal bovine serum (FBS), and arrested cell cycle progression in the S and G 2 /M phases. The same concentrations of platonin significantly inhibited the phosphorylation of JNK1/2 but not ERK1/2 or AKT in VSMCs stimulated by PDGF-BB. Furthermore, platonin also attenuated c-Jun phosphorylation and markedly reversed the down-regulation of p27 expression after PDGF-BB stimulation. Conclusion: Platonin inhibited VSMC proliferation, possibly via inhibiting phosphorylation of JNK1/2 and c-Jun, and reversal of p27 down-regulation, thereby leading to cell cycle arrest at the S and G 2 /M phases. Thus, platonin may represent a novel approach for lowering the risk of abnormal VSMC proliferation and related vascular diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Platonin inhibited PDGF-BB-induced proliferation of rat vascular smooth muscle cells via JNK1/2-dependent signaling

Chang

Uen²,

Chen

et al. 2011

Acta Pharmacol Sin

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“…Alternatively, JNK may mediate Ang II-induced VSMC migration through c-Jun phosphorylation, because c-Jun as well as JNK is required for VSMC migration in response to PDGF. 39,8 Also, because the ERK cascade activation operated through EGFR transactivation is required for Ang II-induced VSMC migration, 40 it is likely that parallel ERK cascade activation together with the JNK cascade activation coordinately induce the migratory responses in VSMCs.…”

Section: Discussionmentioning

confidence: 99%

Signal-Crosstalk Between Rho/ROCK and c-Jun NH ₂ -Terminal Kinase Mediates Migration of Vascular Smooth Muscle Cells Stimulated by Angiotensin II

Ohtsu

Mifune

Frank

et al. 2005

ATVB

112

105

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Background-Rho and its effector Rho-kinase/ROCK mediate cytoskeletal reorganization as well as smooth muscle contraction. Recent studies indicate that Rho and ROCK are critically involved in vascular remodeling. Here, we tested the hypothesis that Rho/ROCK are critically involved in angiotensin II (Ang II)-induced migration of vascular smooth muscle cells (VSMCs) by mediating a specific signal cross-talk. Methods and Results-Immunoblotting demonstrated that Ang II stimulated phosphorylation of a ROCK substrate, regulatory myosin phosphatase targeting subunit (MYPT)-1. Phosphorylation of MYPT-1 as well as migration of VSMCs induced by Ang II was inhibited by dominant-negative Rho (dnRho) or ROCK inhibitor, Y27632. Ang II-induced c-Jun NH 2 -terminal kinase (JNK) activation, but extracellular signal-regulated kinase (ERK) activation was not mediated through Rho/ROCK. Thus, infection of adenovirus encoding dnJNK inhibited VSMC migration by Ang II. We have further demonstrated that the Rho/ROCK activation by Ang II requires protein kinase C-␦ (PKC␦) and proline-rich tyrosine kinase 2 (PYK2) activation, but not epidermal growth factor receptor transactivation. Also, VSMCs express PDZ-Rho guanine nucleotide exchange factor (GEF) and Ang II stimulated PYK2 association with tyrosine phosphorylated PDZ-RhoGEF. A ngiotensin II (Ang II) has been implicated in various cardiovascular diseases such as hypertension, atherosclerosis, and restenosis after angioplasty. 1 Therefore, there has been considerable interest in defining the functional significance of signaling pathways of the Ang II type 1 receptor (AT 1 ), which is dominantly expressed in vascular smooth muscle cells (VSMCs). 1-3 Through this receptor, Ang II stimulates hypertrophy and hyperplasia of VSMCs. 2 The AT 1 receptor primarily couples to G q leading to elevation of intracellular Ca 2ϩ and activation of protein kinase C (PKC). 2 In addition, tyrosine kinase activation by Ang II is linked to downstream mitogenactivated protein kinase (MAPK) activation, thereby mediating the growth promoting response in VSMCs. 2,4,5 In this regard, several key tyrosine kinases have been identified that may contribute to the growth-promoting effects of the AT 1 receptor. These kinases include epidermal growth factor receptor (EGFR) and proline-rich tyrosine kinse 2 (PYK2). 4,5 In addition to its growth responses, VSMC migration by Ang II is strongly implicated in various cardiovascular diseases, 6 whereas the detailed signaling mechanisms by which the AT 1 receptor mediates migration are insufficiently characterized. At least, a MAPK, ERK appears to be required for Ang II-induced migration of VSMCs. 7 Recently, Zahn et al showed that 3 major MAPKs, ERK, p38MAPK, and c-Jun NH 2 -terminal kinase (JNK), are all required for VSMC migration induced by platelet-derived growth factor (PDGF), 8 suggesting that these MAPKs coordinately mediate VSMC migration. A small G protein, Rho, and its effector Rho-kinase/ ROCK, are involved in many aspects of cell motility, from smooth muscle...

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“…85 Protein kinase C, proline-rich tyrosine kinase-2 (PYK2), and Rho/ROCK were found to be upstream of JNK activation and cell migration, but the downstream targets of JNK are less clear. C-Jun has been reported to be necessary for PDGF-induced VSM migration, 136 but how this protein affects migration is unknown. JNK can phosphorylate microtubule-associated proteins and paxillin.…”

Section: Mitogen-activated Protein Kinasesmentioning

confidence: 99%

Mechanisms of Vascular Smooth Muscle Cell Migration

Gerthoffer

2007

Circulation Research

407

350

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Abstract-Smooth muscle cell migration occurs during vascular development, in response to vascular injury, and during atherogenesis. Many proximal signals and signal transduction pathways activated during migration have been identified, as well as components of the cellular machinery that affect cell movement. In this review, a summary of promigratory and antimigratory molecules belonging to diverse chemical and functional families is presented, along with a summary of key signaling events mediating migration. Extracellular molecules that modulate migration include small biogenic amines, peptide growth factors, cytokines, extracellular matrix components, and drugs used in cardiovascular medicine. Promigratory stimuli activate signal transduction cascades that trigger remodeling of the cytoskeleton, change the adhesiveness of the cell to the matrix, and activate motor proteins. This review focuses on the signaling pathways and effector proteins regulated by promigratory and antimigratory molecules. Prominent pathways include phosphatidylinositol 3-kinases, calcium-dependent protein kinases, Rho-activated protein kinase, p21-activated protein kinases, LIM kinase, and mitogen-activated protein kinases. Important downstream targets include myosin II motors, actin capping and severing proteins, formins, profilin, cofilin, and the actin-related protein-2/3 complex. Actin filament remodeling, focal contact remodeling, and molecular motors are coordinated to cause cells to migrate along gradients of chemical cues, matrix adhesiveness, or matrix stiffness. The result is recruitment of cells to areas where the vessel wall is being remodeled. Vessel wall remodeling can be antagonized by common cardiovascular drugs that act in part by inhibiting vascular smooth muscle cell migration. Several therapeutically important drugs act by inhibiting cell cycle progression, which may reduce the population of migrating cells. (Circ Res. 2007;100:607-621.)

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Dominant Negative c-Jun Inhibits Platelet-Derived Growth Factor-Directed Migration by Vascular Smooth Muscle Cells

Cited by 23 publications

References 16 publications

Platonin inhibited PDGF-BB-induced proliferation of rat vascular smooth muscle cells via JNK1/2-dependent signaling

Platonin inhibited PDGF-BB-induced proliferation of rat vascular smooth muscle cells via JNK1/2-dependent signaling

Signal-Crosstalk Between Rho/ROCK and c-Jun NH ₂ -Terminal Kinase Mediates Migration of Vascular Smooth Muscle Cells Stimulated by Angiotensin II

Mechanisms of Vascular Smooth Muscle Cell Migration

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Dominant Negative c-Jun Inhibits Platelet-Derived Growth Factor-Directed Migration by Vascular Smooth Muscle Cells

Cited by 23 publications

References 16 publications

Platonin inhibited PDGF-BB-induced proliferation of rat vascular smooth muscle cells via JNK1/2-dependent signaling

Platonin inhibited PDGF-BB-induced proliferation of rat vascular smooth muscle cells via JNK1/2-dependent signaling

Signal-Crosstalk Between Rho/ROCK and c-Jun NH 2 -Terminal Kinase Mediates Migration of Vascular Smooth Muscle Cells Stimulated by Angiotensin II

Mechanisms of Vascular Smooth Muscle Cell Migration

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Signal-Crosstalk Between Rho/ROCK and c-Jun NH ₂ -Terminal Kinase Mediates Migration of Vascular Smooth Muscle Cells Stimulated by Angiotensin II