Tumor Suppressor p53 But Not cGMP Mediates NO-Induced Expression of p21<sup><i>Waf1/Cip1/Sdi1</i></sup> in Vascular Smooth Muscle Cells

Ishida, Akio; Sasaguri, Toshiyuki; Miwa, Yoshiro; Kosaka, Chiya; Taba, Yoji; Abumiya, Takeo

doi:10.1124/mol.56.5.938

Cited by 31 publications

(28 citation statements)

References 35 publications

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“…p38 MAPK Dependence of NO ⅐ Effects on p21/Waf1 and PLK1 Gene Expression-NO ⅐ has been shown to regulate the expression of a number of cell cycle genes including p21/Waf1 in a variety of cell types (15,29). Consistent with this, p21/Waf1 mRNA was 2-fold up-regulated by GSNO compared with GSH control (p ϭ 0.0001; Fig.…”

Section: Resultssupporting

confidence: 70%

“…Experiments in rodents have found, with a few notable exceptions (18,30), that NO ⅐ controls the cell cycle through cGMP. In contrast, the anti-proliferation effects of NO ⅐ in human cells have been more frequently associated with cGMP-independent signaling (29,31). Consistent with this, our recent microarray study in U937 cells, revealed that NO ⅐ exerts broad control over the cell cycle and cell proliferation through cGMP-independent mechanisms (15).…”

Section: Discussionsupporting

confidence: 65%

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Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

Zhang

Wang

Kern

et al. 2007

Journal of Biological Chemistry

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Polo-like kinase 1 (PLK1) is an evolutionarily conserved serine/threonine kinase essential for cell mitosis. As a master cell cycle regulator, p21/Waf1 plays a critical role in cell cycle progression. Nitric oxide (NO ⅐ ) has been shown to down-regulate PLK1 and up-regulate p21/Waf1 independent of cGMP. Here, the respective roles of p38 MAPK and p21/Waf1 in NO ⅐ -mediated PLK1 repression were investigated using differentiated U937 cells that lack soluble guanylate cyclase. NO ⅐ was shown to down-regulate both PLK1 mRNA and protein. Nuclear run-on assays and mRNA stability studies demonstrated that the effect of NO ⅐ on PLK1 expression was associated with decreased transcription without changes in transcript stability. SB202190, a p38 MAPK inhibitor, prevented transcriptional repression of PLK1 by NO ⅐ . Transfection with dominant-negative p38 MAPK mutant eliminated the NO ⅐ effect on both p21/Waf1 and PLK1 gene expression. Knockdown of p21/Waf1 with siRNA also substantially reduced the regulatory effect of NO ⅐ on PLK1. Reporter gene experiments showed that NO ⅐ decreased activity of the PLK1 proximal promoter, an effect that was blocked by p38 MAPK inhibitor. Deletion or mutation of the CDE/CHR promoter site, an element regulated by p21/Waf1, increased base-line promoter activity and abolished NO ⅐ repression of the PLK1 promoter. Likewise, electrophoretic mobility shift assays with CDE/CHR probe revealed a NO ⅐ -mediated change in protein-probe complex formation. Competition with various unlabeled CDE/CHR mutant sequences showed that NO ⅐ increased nuclear protein binding to intact CHR. These results demonstrate that a NO ⅐ -p38 MAPK-p21/Waf1 signal transduction pathway represses PLK1 through a canonical CDE/CHR promoter element.

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Section: Resultssupporting

confidence: 70%

Section: Discussionsupporting

confidence: 65%

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

Zhang

Wang

Kern

et al. 2007

Journal of Biological Chemistry

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“…p21 is induced by several physiological stimuli that inhibit cell proliferation (Gartel et al, 1996), such as nerve growth factor, transforming growth factor-␤, interferons, 1,25-dihydroxyvitamin D 3 , retinoids, PGA 2 , nitric oxide (Ishida et al, 1997(Ishida et al, , 1999, and fluid shear stress loaded on vascular endothelial cells (Akimoto et al, 2000). However, substances that inhibit cyclin D1 expression are rare , let alone those that also induce p21.…”

Section: Discussionmentioning

confidence: 99%

15-Deoxy-Δ^12,14-prostaglandin J₂Induces G₁Arrest and Differentiation Marker Expression in Vascular Smooth Muscle Cells

et al. 2000

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In search of substances useful for the treatment of atherosclerotic vascular diseases, we studied the effects of 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), a natural ligand for peroxisome proliferator-activated receptor ␥, on the proliferation and differentiation of vascular smooth muscle cells (VSMCs). 15d-PGJ 2 but not WY14643, an agonist for peroxisome proliferatoractivated receptor ␣, dose-dependently inhibited VSMC proliferation; the effect was maximal at 12 M. This compound strongly suppressed the activities of cyclin-dependent kinases (Cdk) 4, 6, and 2, thereby preventing the phosphorylation of the retinoblastoma protein. These Cdks seemed to be inhibited through two mechanisms: the down-regulation of cyclin D1 and the up-regulation of Cdk inhibitor p21Cip1/Waf1/Sdi1 . 15d-PGJ 2 was found to inhibit the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which mediates cyclin D1 expression. Mitogenic stimulation of quiescent cells decreased the level of mRNA for the smooth muscle-specific myosin heavychain SM1, whereas this reduction was prevented by 15d-PGJ 2 . A long-term treatment of exponentially growing VSMCs with 15d-PGJ 2 markedly elevated the mRNA level of SM1 and, moreover, induced SM2, another isoform expressed exclusively in mature VSMCs. 15d-PGJ 2 also increased the expression levels of calponin-h1 and smooth muscle ␣-actin. These results suggest that 15d-PGJ 2 induces G 1 arrest by two distinct mechanisms and promotes VSMC differentiation.Vascular smooth muscle cells (VSMCs) in the arterial media are fully differentiated to play their physiological roles as regulators of vascular wall tension. However, in atherosclerotic and restenotic lesions, their phenotypes have been converted to dedifferentiated (immature) ones (Owens, 1995). Dedifferentiated VSMCs migrate into the intima, proliferate, and synthesize extracellular matrices, thereby contributing to the formation of neointima. Therefore, to prevent VSMC hyperplasia in vivo, substances capable of promoting the differentiation of VSMCs may be more effective than those that simply inhibit their proliferation. A number of substances have been reported to inhibit VSMC proliferation, but few are also able to prevent phenotype conversion and induce differentiation.Prostaglandins (PGs) of the J 2 family, including PGJ 2 , ⌬ 12 -PGJ 2 , and 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), are naturally occurring metabolites of PGD 2 (Kikawa et al., 1984). We previously reported that PGJ 2 and ⌬ 12-PGJ 2 strongly inhibit VSMC proliferation, although the underlying mechanisms remain undetermined (Sasaguri et al., 1992). Recently, PGs of the J 2 family were found to be natural ligands for peroxisome proliferator-activated receptor (PPAR) ␥, a member of the ligand-activated transcription factor nuclear receptor superfamily that includes receptors for steroid, retinoid, and thyroid hormones (Forman et al., 1995;Kliewer et al., 1995). PPAR␥ has been implicated in the induction of differentiation in adipocytes (Forman et al.,...

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“…Using 1 g of this RNA, the L-PGDS mRNA expression was analyzed by RT-PCR using the Ready-To-Go RT-PCR Beads (Amersham Biosciences), 16,23 and PCR primers were synthesized on the basis of the information obtained from the GenBank database.…”

Section: Reverse Transcription-pcrmentioning

confidence: 99%

Activator Protein-1 Mediates Shear Stress–Induced Prostaglandin D Synthase Gene Expression in Vascular Endothelial Cells

Matsumoto

Miwa

Takahashi-Yanaga

et al. 2005

ATVB

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Objective-We attempted to determine the molecular mechanism of fluid shear stress-induced lipocalin-type prostaglandin D synthase (L-PGDS) expression in vascular endothelial cells. Methods and Results-We examined the promoter region of the L-PGDS gene by loading laminar shear stress (20 dyne/cm 2 ), using a parallel-plate flow chamber, on endothelial cells transfected with luciferase reporter vectors containing the 5Ј-flanking regions of the human L-PGDS gene. A deletion mutant analysis revealed that a shear stress-responsive element resided in the region between Ϫ2607 and Ϫ2523 bp. A mutation introduced into the putative binding site for activator protein-1 (AP-1) within this region eliminated the response to shear stress. In an electrophoretic mobility shift assay, shear stress stimulated nuclear protein binding to the AP-1 binding site, which was supershifted by antibodies to c-Fos and c-Jun. Shear stress elevated the c-Jun phosphorylation level in a time-dependent manner, similar to that of L-PGDS gene expression. SP600125, a c-Jun N-terminal kinase inhibitor, decreased the c-Jun phosphorylation, DNA binding of AP-1, and L-PGDS expression induced by shear stress. Additionally, an mRNA chase experiment using actinomycin D demonstrated that shear stress did not stabilize L-PGDS mRNA. applied in vitro prevents platelet aggregation 1 and induces endothelium-dependent arterial relaxation. 2 PGD 2 is metabolized to the PGJ 2 family, which includes PGJ 2 , ⌬ 12 -PGJ 2 , and 15-deoxy-⌬ 12,14 -PGJ 2 (15d-PGJ 2 ), without the requirement of specific enzymes. 3 The PGJ 2 family, particularly 15d-PGJ 2 , exhibits strong anti-inflammatory effects by inhibiting nuclear factor B 4 and IB kinase 5 or through the activation of a peroxisome proliferator-activated receptor-␥. 6 In macrophages, 15d-PGJ 2 inhibits inflammatory cytokine production, metalloproteinase-9 activation, and inducible NO synthase expression. 7,8 The PGJ 2 family strongly inhibits vascular smooth muscle cell proliferation and promotes smooth muscle cell differentiation. 9 -11 In vascular endothelial cells, 15d-PGJ 2 inhibits apoptotic cell death by upregulating the caspase inhibitor cellular inhibitor of apoptosis protein 1 (c-IAP1). 12 The majority of the effects induced by PGD 2 and the PGJ 2 family members appear to be anti-inflammatory, and therefore atheroprotective, because atherosclerosis is considered to be a chronic inflammation in vascular cells and tissues. 13 Lipocalin-type PGD synthase (L-PGDS) catalyzes the isomeric conversion of PGH 2 to PGD 2 . 14 In human cardiovascular tissues, the L-PGDS mRNA is most strongly expressed in the heart, where immunoreactivity of the enzyme is localized in the myocardial and endocardial cells. 15 Human aortic endothelial cells and intimal smooth muscle cells in vivo also stain positive for the L-PGDS mRNA by in situ hybridization. 16 Recent studies have suggested relationships between L-PGDS and cardiovascular diseases. For example, L-PGDS is secreted into the coronary circulation in angina patients. 15 Ele...

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Tumor Suppressor p53 But Not cGMP Mediates NO-Induced Expression of p21^{Waf1/Cip1/Sdi1} in Vascular Smooth Muscle Cells

Cited by 31 publications

References 35 publications

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

15-Deoxy-Δ^12,14-prostaglandin J₂Induces G₁Arrest and Differentiation Marker Expression in Vascular Smooth Muscle Cells

Activator Protein-1 Mediates Shear Stress–Induced Prostaglandin D Synthase Gene Expression in Vascular Endothelial Cells

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Tumor Suppressor p53 But Not cGMP Mediates NO-Induced Expression of p21Waf1/Cip1/Sdi1 in Vascular Smooth Muscle Cells

Cited by 31 publications

References 35 publications

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

15-Deoxy-Δ12,14-prostaglandin J2Induces G1Arrest and Differentiation Marker Expression in Vascular Smooth Muscle Cells

Activator Protein-1 Mediates Shear Stress–Induced Prostaglandin D Synthase Gene Expression in Vascular Endothelial Cells

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Tumor Suppressor p53 But Not cGMP Mediates NO-Induced Expression of p21^{Waf1/Cip1/Sdi1} in Vascular Smooth Muscle Cells

15-Deoxy-Δ^12,14-prostaglandin J₂Induces G₁Arrest and Differentiation Marker Expression in Vascular Smooth Muscle Cells