Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AIDS-associated Kaposi's sarcoma (KS) cell, a key element for development of KS lesions, proliferates in response to external cytokines, such as oncostatin M, the soluble IL-6R-IL-6 complex, TNF-alpha, and IL-1beta. In addition, the KS cell-produced basic fibroblast growth factor (bFGF) was reported to function as an autocrine growth factor. However, little is known of the exact roles of these external growth factors and endogenous bFGF on proliferation of KS cells, and underlying intracellular events have remained to be defined. We obtained evidence that anti-bFGF Ab abolished growth of KS cells by preventing S phase entry of the cell cycle, even in the presence of the external growth factors. Blockade of the FGF action profoundly inhibited cyclin E expression and cyclin-dependent kinase-2 (CDK2) activity, but not D-type cyclin expression and CDK4 activity. Exogenously added acidic FGF (aFGF), which generated a rapid tyrosine phosphorylation of FGFR1 and FGFR2 on KS cells, reversed the inhibitory effects of anti-bFGF Ab. Thus, FGF actions are essential for cyclin E-CDK2 activity and S phase entry. We also observed that the presence of external growth factors markedly induced cyclin E-CDK2 activity and S phase entrance, while the addition of aFGF or bFGF alone was insufficient to induce these responses. All this evidence shows that integration of the activities of external growth factors and endogenous bFGF is required for full activation of cyclin E-CDK2 activity and KS cell proliferation.
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PMID:Endogenous basic fibroblast growth factor is essential for cyclin E-CDK2 activity in multiple external cytokine-induced proliferation of AIDS-associated Kaposi's sarcoma cells: dual control of AIDS-associated Kaposi's sarcoma cell growth and cyclin E-CDK2 activity by endogenous and external signals. 971 33

The deoxyadenosine-resistant mouse leukemia L1210 cell line (Y8) has previously been shown to have phenotypic differences that appear to be unrelated to the altered properties observed at the level of ribonucleotide reductase (RR). One of these changes is that the Y8 cells do not express p53. In response to DNA damaging agents, x-irradiation and doxorubicin, both the parental wild-type L1210 (WT) and Y8 cells undergo G2/M arrest, which is consistent with cells lacking wild-type p53 function. However, Y8 cells are much more sensitive to apoptosis induced by these agents than WT cells. Previous studies have also shown that expression of certain genes involved in cell cycle regulation is different between WT and Y8 cells. Recent evidence suggests that a serine/threonine kinase is involved in the divergent cellular responses of these cells. In the present study, the effects of roscovitine, a cyclin-dependent kinase inhibitor, were examined on the WT and Y8 cells. The WT cells blocked in G2/M, whereas Y8 cells became apoptotic. Apoptosis induced by roscovitine in the Y8 cells was mediated by a caspase-3-like activity. NF kappa B was activated to a much greater extent by roscovitine in the WT cells than in Y8 cells. The data also indicate that cyclin B1/cdc2 plays a role in the divergent p53-independent G2/M block and apoptotic responses of the WT and Y8 cells, respectively. Several key factors such as cathepsin B, caspase-1, release of cytochrome c into the cytosol, TNF-alpha signaling, FasL/Fas signaling, c-myc overexpression, and E2F-1 overexpression and induction were shown not to be involved in the apoptotic pathway(s) in the Y8 cells.
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PMID:Enhanced roscovitine-induced apoptosis is mediated by a caspase-3-like activity in deoxyadenosine-resistant mouse leukemia L1210 cells. 1113 34

It has been observed that liver regeneration in acute hepatic failure (AHF) is suppressed [Eguchi et al. Hepatology 1996;24(6):1452-9]. The molecular mechanism regulating this inhibition is not known. We previously reported that in AHF rats, hepatocyte proliferation was significantly impaired with elevation in serum IL-6, TGF-beta1, and HGF [Kamohara et al. Biochem Biophys Res Commun 2000;273(1):129-35]. Following either 70% partial hepatectomy (PH) or liver injury, quiescent mature hepatocytes are "primed" to re-enter the cell cycle. The process of "priming" appears to be triggered by extracellular cytokines (IL-6 and TNF-alpha) and is characterized by expression of immediate early genes. Under the stimulation of growth factors such as HGF, "primed" hepatocytes exit the G1 phase of the cell cycle. G1-associated cyclins and their inhibitors play a pivotal role in G1/S cell cycle transition. Here, we demonstrate that immediate early gene (i.e. c-myc, c-fos) expression and AP-1 activity are preserved in AHF rat livers despite absence of hepatocyte proliferation. In contrast, p21 mRNA and protein are both over-expressed in AHF livers compared to livers from rats undergoing PH; this elevation leads to inhibition in Cdk2 activity, resulting in G1 cell cycle arrest and inhibition of regeneration.
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PMID:Immediate early genes and p21 regulation in liver of rats with acute hepatic failure. 1197 36

Liver regeneration after partial hepatectomy (PH) involves several signaling mechanisms including activation of the small GTPases Ras and RhoA in response to mitogens leading to DNA synthesis and cell proliferation. Peroxisome proliferator-activated receptor-alpha (PPARalpha) regulates the expression of several key enzymes in isoprenoid synthesis, which are key events for membrane association of Ras and RhoA. Thus the role of PPARalpha in cell proliferation after PH was tested. After PH, an increase in PPARalpha DNA binding was observed in wild-type mice, correlating with an increase in the PPARalpha-regulated enzyme acyl-CoA oxidase. In addition, the PPARalpha-regulated genes farnesyl pyrophosphate synthase and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase were significantly increased in wild-type mice. However, these increases were not observed in PPARalpha knockout (PPARalpha -/-) mice. The peak in DNA synthesis observed 42 h after PH was reduced by approximately 60% in PPARalpha -/- mice, despite increases in TNF-alpha and IL-1. Also, under these conditions, membrane association of Ras was high in wild-type mice after PH but was impaired in PPARalpha -/- mice. Accordingly, Ras was significantly elevated in the cytosol in PPARalpha -/- mice. This observation correlated with lower levels of active GTP-bound Ras after PH in PPARalpha -/- mice compared with wild-type mice. Similar observations were made for RhoA. Moreover, deletion of PPARalpha blunted the activation of cyclin-dependent kinase (cdk)2/cyclin E and cdk4/cyclin D complexes. Collectively, these results support the hypothesis that PPARalpha is necessary for cell cycle progression in regenerating mouse liver via mechanisms involving prenylation of small GTPases Ras and RhoA.
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PMID:Impaired Ras membrane association and activation in PPARalpha knockout mice after partial hepatectomy. 1238 8

The French paradox has been attributed to the antioxidant properties of flavonoids present in the red wine. Quercetin, a bioflanoid present in the human diet, is known to inhibit angiotensin II-induced hypertrophy and serum-induced smooth muscle cell proliferation. However, it is not known whether quercetin exerts similar cardioprotective effects in cells treated with TNF-alpha. In this study, we investigated whether quercetin exerts the multiple suppressive effects on cytokine TNF-alpha-induced human aortic smooth muscle cells (HASMC). Treatment of quercetin showed potent inhibitory effects on the DNA synthesis of cultured HASMC in the presence of TNF-alpha. These inhibitory effects were associated with reduced extracellular signal-regulated kinase (ERK)1/2 activity and G1 cell-cycle arrest. Treatment of quercetin, which induced a cell-cycle block in G1-phase, induced down-regulation of cyclins and CDKs and up-regulation of the CDK inhibitor p21 expression, whereas up-regulation of p27 or p53 by quercetin was not observed. Because anti-atherogenic effects need not be limited to antiproliferation, we decided to examine whether quercetin exerted inhibitory effects on matrix metalloproteinase-9 (MMP-9) activity in TNF-alpha-induced HASMC. Quercetin inhibited TNF-alpha-induced MMP-9 secretion on HASMC in a dose-dependent manner. This inhibition was characterized by down-regulation of MMP-9, which was transcriptionally regulated at NF-kappaB site and activation protein-1 (AP-1) site in the MMP-9 promoter. These findings indicate the efficacy of quercetin in inhibiting cell proliferation, G1- to S-phase cell-cycle progress, and MMP-9 expression through the transcription factors NF-kappaB and AP-1 on TNF-alpha-induced HASMC.
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PMID:Quercetin exerts multiple inhibitory effects on vascular smooth muscle cells: role of ERK1/2, cell-cycle regulation, and matrix metalloproteinase-9. 1258 22

Hepatocyte proliferation represents an important part of tissue repair. In these studies, TNF receptor 1 (TNFR1) knockout mice were used to analyze the role of TNF-alpha in hepatocyte proliferation during acetaminophen-induced hepatotoxicity. Treatment of wild-type (WT) mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis. This was associated with proliferation of hepatocytes surrounding the damaged areas, which was evident at 24 h. The cell cycle regulatory proteins, cyclin D1 and cyclin A, were also up regulated in hepatocytes. In contrast, in TNFR1-/- mice, which exhibit exaggerated acetaminophen hepatotoxicity, hepatocyte proliferation, and expression of cyclin D1 and cyclin A, as well as the cyclin dependent kinases, Cdk4 and Cdk2, were reduced. The cyclin-dependent kinase inhibitor p21 was also induced in the liver following acetaminophen administration. This was greater in TNFR1-/- mice compared to WT mice. To investigate mechanisms mediating the reduced hepatic proliferative response of TNFR1-/- mice, we analyzed phosphatidyl inositol-3-kinase (PI-3K) signaling. In both WT and TNFR1-/- mice, acetaminophen caused a rapid increase in total PI-3K within 3 h. Acetaminophen also increased phosphorylated PI-3K, but this was delayed 6-12 h in TNFR1-/- mice. Expression of Akt, a downstream target of PI-3K, was increased in both WT and TNFR1-/- mice in response to acetaminophen. However, the increase was greater in WT mice. Acetaminophen-induced expression of phosphorylated STAT3, a key regulator of cytokine-induced hepatocyte proliferation, was also delayed in TNFR1-/- mice relative to WT. These data suggest that TNF-alpha signaling through TNFR1 is important in regulating hepatocyte proliferation following acetaminophen-induced tissue injury. Delayed cytokine signaling may account for reduced hepatocyte proliferation and contribute to exaggerated acetaminophen-induced hepatotoxicity in TNFR1-/- mice.
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PMID:Role of tumor necrosis factor receptor 1 (p55) in hepatocyte proliferation during acetaminophen-induced toxicity in mice. 1464 24

The tumor suppressor PTEN is one of the most commonly inactivated genes in human cancer. PTEN, an inositol phosphatase specific for the products of PI 3-kinase, is known to inhibit PDGF-mediated vascular smooth muscle cell (VSMC) proliferation and migration. However, little is known about the molecular mechanisms by which this tumor suppressor regulates cell growth and migration in VSMC. Here, we show that PTEN expression has the potent inhibitory effect on DNA synthesis of cultured VSMC in the presence of PDGF. The growth suppression of PTEN was mediated by its ability to block cell cycle progression in the G1 phase. Such an arrest correlated with down-regulation of cyclins and CDKs and up-regulation of the CDK inhibitor p21 and p27 expression, whereas up-regulation of p53 by PTEN expression was not observed. Expression of PTEN also led to the inhibition of TNF-alpha-induced matrix metalloproteinase-9 (MMP-9) expression in VSMC as determined by zymography and immunoblot. Furthermore, PTEN expression strongly decreased MMP-9 promoter activity in response to TNF-alpha. This inhibition was characterized by down-regulation of MMP-9, which was transcriptionally regulated at NF-kappaB and activation protein-1 (AP-1) sites in the MMP-9 promoter. These findings indicate the efficacy of PTEN in inhibiting cell proliferation, G1-S phase cell cycle progress, and MMP-9 expression through the transcription factors NF-kappaB and AP-1 in VSMC.
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PMID:PTEN induces G1 cell cycle arrest and inhibits MMP-9 expression via the regulation of NF-kappaB and AP-1 in vascular smooth muscle cells. 1498 7

Sialic acid-containing glycosphingolipids (gangliosides) have been implicated in the regulation of various biological phenomena such as atherosclerosis. Recent report suggests that exogenously supplied disialoganglioside (GD3) serves a dual role in vascular smooth muscle cells (VSMC) proliferation and apoptosis. However, the role of the GD3 synthase gene in VSMC responses has not yet been elucidated. To determine whether a ganglioside is able to modulate VSMC growth, the effect of overexpression of the GD3 synthase gene on DNA synthesis was examined. The results show that the overexpression of this gene has a potent inhibitory effect on DNA synthesis and ERK phosphorylation in cultured VSMC in the presence of PDGF. The suppression of the GD3 synthase gene was correlated with the down-regulation of cyclinE/CDK2, the up-regulation of the CDK inhibitor p21 and blocking of the p27 inhibition, whereas up-regulation of p53 as the result of GD3 synthase gene expression was not observed. Consistently, blockade of GD3 function with anti-GD3 antibody reversed VSMC proliferation and cell cycle proteins. The expression of the GD3 synthase gene also led to the inhibition of TNF-alpha-induced matrix metalloproteinase-9 (MMP-9) expression in VSMC as determined by zymography and immunoblot. Furthermore, GD3 synthase gene expression strongly decreased MMP-9 promoter activity in response to TNF-alpha. This inhibition was characterized by the down-regulation of MMP-9, which was transcriptionally regulated at NF-kappaB and activation protein-1 (AP-1) sites in the MMP-9 promoter. Finally, the overexpression of MMP-9 in GD3 synthase transfectant cells rescued VSMC proliferation. However, MMP-2 overexpression was not affected by cell proliferation. These findings suggest that the GD3 synthase gene represents a physiological modulator of VSMC responses that may contribute to plaque instability in atherosclerosis.
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PMID:Disialoganglioside (GD3) synthase gene expression suppresses vascular smooth muscle cell responses via the inhibition of ERK1/2 phosphorylation, cell cycle progression, and matrix metalloproteinase-9 expression. 1517 38

Previous studies demonstrated that live Bartonella quintana often induces angioproliferative lesions in humans. It modulates endothelial cell apoptotic and inflammatory patterns, thus inducing a very early overexpression of caspase 8 and Apaf-1 and increasing mRNA production of TNF-alpha, interleukin-8, and E-selectin. However, starting at 10 hours postinfection, the bacteria provoke antiapoptotic effects that induce an increase of bcl-2 gene transcription. To gain further insight into the cellular mechanisms that regulate apoptosis, survival and proliferation, we studied the modulation of mitogen-activated protein kinase (MAPK) and the activation state of cdc2 kinase, which regulates progression into mitosis. Confocal microscopy findings indicated a maximum rate of Bartonella entry into host cells between postinfection hours 6 and 10. Live bacteria caused substantially higher apoptosis of human umbilical vein endothelial cells-cryopreserved (HUVEC-C) than heat- and trypsin-inactivated microorganisms. During the first 6 hours postinfection, B. quintana triggered a peak of apoptosis, induced activation of p38 MAPK and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), with bacterial clusters appearing at the cellular surface of the HUVEC-C. However, at 8 to 24 hours postinfection, B. quintana was internalized and inhibited proapoptotic signals such as p38 MAPK and SAPK/JNK while inducing antiapoptotic signals. Indeed, expression of the bcl-2 gene and the increase of the bcl-2 kinase active form was concomitant to activation of mitosis, as shown by cdc2 protein activation. These data thus suggest that mechanisms that induce mitotic activity and inhibit apoptotic signals may contribute to the ability of B. quintana to cause vascular proliferation.
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PMID:Bartonella quintana-induced apoptosis inhibition of human endothelial cells is associated with p38 and SAPK/JNK modulation and with stimulation of mitosis. 1554

Dietary isothiocyanates (ITCs) have shown protective effects against certain chemically induced cancers in animal models. These inhibitory effects are associated with reduced levels of extracellular signal-regulated kinase (ERK) 1/2 activity and the arrest of the G(1) cell cycle. Benzyl isothiocyanate (BITC) treatment down-regulates cyclins and CDKs and up-regulates the expression of the CDK inhibitor p21, but up-regulation of p27 or p53 was not detected. Since antiatherogenic effects are not needed for antiproliferation, we determined whether BITC exerted inhibitory effects on matrix metalloproteinase-9 (MMP-9) activity in TNF-alpha-induced vascular smooth muscle cells (VSMCs). BITC inhibited TNF-alpha-induced MMP-9 secretion in VSMC in a dose dependent manner. This inhibition was characterized by the down-regulation of MMP-9, which is transcriptionally regulated at the NF-kappaB site, and the activation protein-1 (AP-1) site in the MMP-9 promoter. These findings indicate that BITC is an effective agent for inhibiting cell proliferation, the G1 to S phase cell cycle progress, and MMP-9 expression through the transcription factors NF-kappaB and AP-1 in TNF-alpha-induced VSMC.
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PMID:A novel function of benzyl isothiocyanate in vascular smooth muscle cells: the role of ERK1/2, cell cycle regulation, and matrix metalloproteinase-9. 1560 68


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