UNIPROT:P05412 - FACTA Search

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SU5416 is reported to be a selective inhibitor of vascular endothelial growth factor, and it has metwith limited success in the clinic. In the present study, we investigated whether SU5416 could augment cisplatin-induced cytotoxicity in human ovarian cancer cells. When used as a single agent, 2-h exposures to SU5416 were not harmful to the cells up to doses of 100 microM. For 48-h exposures, the SU5416 IC20 and IC50 were 17 and 34 microM, respectively. When used with cisplatin, the effect of SU5416 was sequence dependent. SU5416 given first was subadditive, whereas cisplatin given first was supraadditive. Cisplatin was given as a 1-h exposure. Augmented cisplatin cytotoxicity was seen with 2-h exposures to SU5416 at doses of 17-34 microM. This was associated with a decrease in cisplatin-DNA adduct repair, as measured by atomic absorbance spectrometry. Treatment of the ovarian carcinoma cells with SU5416 was also associated with a reduced expression of ERCC-1 protein and c-jun mRNA, as well as a decrease in c-Jun and JNK activities. We conclude that SU5416 can be used to augment cisplatin-induced cell killing at doses that are non-toxic. This effect may occur through direct or indirect reduction of the activity of AP-1 and DNA repair.
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PMID:SU5416 sensitizes ovarian cancer cells to cisplatin through inhibition of nucleotide excision repair. 1278 26

The incidence of cutaneous malignant melanoma in the United States has increased more than any other cancer in recent years. Chemotherapy for metastatic melanoma is disappointing, there being anecdotal cases of complete remission. Dacarbazine (DTIC) is considered the gold standard for treatment, having a response rate of 15-20%, but most responses are not sustained. The mechanisms for the increased chemotherapeutic resistance of melanoma are unclear. The objective of this study was to determine the mechanisms by which melanoma cells escape the cytotoxic effect of DTIC. Here, we show that DTIC induced interleukin (IL)-8 and vascular endothelial growth factor (VEGF) protein overexpression and secretion via transcriptional up-regulation in the two melanoma cell lines SB-2 and MeWo. Luciferase activity driven by the IL-8 and VEGF promoters was up-regulated by 1.5-2- and 1.6-3.5-fold, respectively, in the SB2 and MeWo melanoma cell lines. The mitogen-activated protein kinase signal transduction pathway seemed to regulate at least partially the activation of IL-8, whereas it was not involved in VEGF promoter regulation. Electrophoretic mobility shift analysis analyses have revealed an increase in binding activity of activator protein 1 (c-Jun) and nuclear factor-kappaB after DTIC treatment for both melanoma cell lines. Metastatic melanoma cell lines secreting high levels of IL-8 and VEGF were more resistant to DTIC than early primary melanomas secreting low levels of the cytokines. In addition, transfection of the primary cutaneous melanoma SB-2 cells with the IL-8 gene rendered them resistant to the cytotoxic effect of the drug, whereas the addition of IL-8-neutralizing antibody to metastatic melanoma cells lowered their sensitivity to DTIC. Taken together, our data demonstrate that DTIC can cause melanoma cells to secrete IL-8 and VEGF, which might render them resistant to the cytotoxic effects of the drug. We propose that combination treatment with anti-VEGF/IL-8 agents may potentiate the therapeutic effects of DTIC.
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PMID:Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. 1502 59

VEGF (vascular endothelial growth factor), an important angiogenesis factor, appears also to be involved in inflammatory processes. Recent studies have shown that VEGF and its receptors (VEGFR) are expressed on osteoarthritic, but not on normal adult, chondrocytes. To elucidate possible functions of VEGF in osteoarthritic cartilage, the effects of VEGF were studied on immortalized human chondrocytes. Activated matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, interleukin (IL)-1beta, IL-6, and tumour necrosis factor-alpha (TNF-alpha) were measured in culture supernatants by enzyme-linked immunosorbent assays, nitric oxide with the Griess reagent, and cell proliferation by [3H]thymidine incorporation. VEGFR-2 mRNA was quantified by real-time reverse transcription-polymerase chain reaction and the protein was identified by immuno-gold electron microscopy. Intracellular signal transduction effects were determined by western blots and electrophoretic mobility shift assays. The chondrocyte cell lines C28/I2, C20/A4, and T/C28a2/a4 expressed functionally active VEGFR-2. VEGF stimulation induced receptor phosphorylation, activation of the mitogen-activated protein kinases ERK 1/2, and long-lasting activation of the transcription factor AP-1 (activator protein-1). VEGF increased secreted MMP-1, MMP-3, and especially MMP-13, which could be effectively reduced by an inhibitor of VEGFR-2 kinase activity. Interestingly, VEGF diminished the expression of TIMP-1 and especially TIMP-2. Under hypoxic conditions, as occur in cartilage, the reduction in TIMP levels was even greater. Furthermore, VEGF induced IL-1beta, IL-6, TNF-alpha, and nitric oxide expression to a small extent and stimulated the proliferation of immortalized chondrocytes. These findings indicate that VEGF is an autocrine stimulator of immortalized chondrocytes that mediates mainly destructive processes in osteoarthritis.
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PMID:Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. 1499 3

We previously reported that prostaglandin E(1) (PGE(1)) activates both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase via cAMP-dependent protein kinase in osteoblast-like MC3T3-E1 cells, and that p38 MAP kinase but not p42/p44 MAP kinase is involved in PGE(1)-induced synthesis of vascular endothelial growth factor (VEGF). In the present study, we investigated the involvement of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in the PGE(1)-induced VEGF synthesis in MC3T3-E1 cells. PGE(1) induced the phosphorylation of SAPK/JNK. SP600125, a specific inhibitor of SAPK/JNK, markedly reduced the PGE(1)-induced VEGF synthesis. Forskolin, a direct activator of adenylyl cyclase, elicited the phosphorylation of SAPK/JNK, and 8bromo-cAMP, a plasma membrane-permeable cAMP analogue-stimulated VEGF synthesis was significantly reduced by SP600125. SP600125 suppressed the PGE(1)-induced phosphorylation of SAPK/JNK without affecting the phosphorylation of p38 MAP kinase induced by PGE(1). The phosphorylation of c-Jun induced by PGE(1) was also inhibited by SP600125. SB203580, a p38 MAP kinase inhibitor, failed to reduce the PGE(1) induced phosphorylation of SAPK/JNK. A combination of SP600125 and SB203580 suppressed the PGE(1)-stimulated VEGF synthesis in an additive manner. These results strongly suggest that PGE(1) activates SAPK/JNK in osteoblasts, and that SAPK/JNK plays a part in PGE(1)-induced VEGF synthesis.
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PMID:Involvement of SAPK/JNK in prostaglandin E(1)-induced VEGF synthesis in osteoblast-like cells. 1519 3

Diabetic retinopathy is a leading cause of blindness in the Western world. Aberrant intercellular adhesion molecule-1 expression and leukocyte adhesion have been implicated in its pathogenesis, raising the possibility of an underlying chronic inflammatory mechanism. In the current study, the role of insulin-like growth factor (IGF)-I in these processes was investigated. We found that systemic inhibition of IGF-I signaling with a receptor-neutralizing antibody, or with inhibitors of PI-3 kinase (PI-3K), c-Jun kinase (JNK), or Akt, suppressed retinal Akt, JNK, HIF-1alpha, nuclear factor (NF)-kappaB, and AP-1 activity, vascular endothelial growth factor (VEGF) expression, as well as intercellular adhesion molecule-1 levels, leukostasis, and blood-retinal barrier breakdown, in a relevant animal model. Intravitreous administration of IGF-I increased retinal Akt, JNK, HIF-1alpha, NF-kappaB, and AP-1 activity, and VEGF levels. IGF-I stimulated VEGF promoter activity in vitro, mainly via HIF-1alpha, and secondarily via NF-kappaB and AP-1. In conclusion, IGF-I participates in the pathophysiology of diabetic retinopathy by inducing retinal VEGF expression via PI-3K/Akt, HIF-1alpha, NF-kappaB, and secondarily, JNK/AP-1 activation. Taken together, these in vitro and in vivo signaling studies thus identify potential targets for pharmacological intervention to preserve vision in patients with diabetes.
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PMID:Insulin-like growth factor-I plays a pathogenetic role in diabetic retinopathy. 1527 20

Cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF) are significantly associated with tumor growth and metastasis. Here we show that phorbol ester-mediated induction of VEGF and COX-2 expression in colon carcinoma cells is inhibited by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)). This cyclopentenone was able to inhibit activator protein1 (AP-1)-dependent transcriptional induction of COX-2 and VEGF promoters induced by phorbol 12-myristate 13-acetate (PMA) or c-Jun overexpression. 15d-PGJ(2) interfered with at least two steps within the signaling pathway leading to AP-1 activation. First, 15d-PGJ(2) impaired AP-1 binding to a consensus DNA sequence. Second, 15d-PGJ(2) selectively inhibited c-Jun NH(2) terminal kinase (JNK) but not extracellular signal-regulated kinase or p38 mitogen-activated protein kinase activation induced by PMA. This led to a decreased ability of JNK to phosphorylate c-Jun and to activate its transactivating activity. Inhibition of AP-1 activation and COX-2 or VEGF transcriptional induction by this cyclopentenone was found to be independent of peroxisome proliferator-activated receptor-gamma (PPARgamma) because it was not affected by either expression of a dominant negative form of PPARgamma or the use of a PPARgamma antagonist. In contrast, we have found that the effects of 15d-PGJ(2) on AP-1 activation may occur through its ability to induce intracellular oxidative stress. The antioxidant N-acetylcysteine significantly reversed the inhibition by 15d-PGJ(2) of AP-1 activity and COX-2 or VEGF transcriptional induction. Together, these findings provide new insight into the antitumoral properties of 15d-PGJ(2) through the inhibition of the induction of AP-1-dependent genes involved in tumor progression, such as COX-2 and VEGF.
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PMID:Inhibition of activator protein 1 activation, vascular endothelial growth factor, and cyclooxygenase-2 expression by 15-deoxy-Delta12,14-prostaglandin J2 in colon carcinoma cells: evidence for a redox-sensitive peroxisome proliferator-activated receptor-gamma-independent mechanism. 1528 20

Topoisomerase I inhibitors are effective anticancer therapies and have shown activity in hematologic malignancies. Here we show for the first time that SN38, the potent active metabolite of irinotecan, induces c-Jun NH(2)-terminal kinase activation, Fas up-regulation, and caspase 8-mediated apoptosis in multiple myeloma (MM) cells. Proteasomal degradation of nuclear topoisomerase I has been proposed as a resistance mechanism in solid malignancies. SN38-induced proteasomal degradation of topoisomerase I was observed during SN38-mediated cytotoxicity against MM.1S myeloma cell line but occurred after c-Jun NH(2)-terminal kinase activation, Fas up-regulation, and poly(ADP-ribose) polymerase cleavage and failed to protect cells from apoptosis. Differential toxicity was observed against MM cells versus bone marrow stromal cells, and SN38 inhibited adhesion-induced up-regulation of MM cell proliferation when MM cells adhere to bone marrow stromal cells. In addition, SN38 directly inhibited constitutive and inducible interleukin 6 and vascular endothelial growth factor secretion by bone marrow stromal cells. Synergy was observed when SN38 was used in combination with doxorubicin, bortezomib, as well as poly(ADP-ribose) polymerase inhibitor NU1025 and Fas-activator CH11. These findings have clinical significance, because identification of downstream apoptotic signaling after topoisomerase I inhibition will both elucidate mechanisms of resistance and optimize future combination chemotherapy against MM.
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PMID:Proteasomal degradation of topoisomerase I is preceded by c-Jun NH2-terminal kinase activation, Fas up-regulation, and poly(ADP-ribose) polymerase cleavage in SN38-mediated cytotoxicity against multiple myeloma. 1557 86

The induction of proangiogenic cytokines such as vascular endothelial growth factor (VEGF) is a critical feature of tumor angiogenesis. In the present study, we examined the mechanisms of VEGF gene expression induced by glucose deprivation in cancer cells, a role of AMP-activated protein kinase (AMPK) in the process, and the signal transduction pathway. AMPK functions as an energy sensor to provide metabolic adaptation under ATP-depleting conditions such as hypoxia and nutritional deprivation. Here, we show that glucose deprivation leads to a significant increase in the mRNA level of VEGF, GLUT1, and PFKFB3 genes in several cancer cells via a hypoxia-inducible factor-1-independent mechanism, and we demonstrate an essential role of AMPK in these gene expressions. Our data suggest that VEGF mRNA induction by glucose deprivation is due to an increase in mRNA stability, and the AMPK activity is necessary and sufficient to confer the stability to VEGF mRNA. We further show that reactive oxygen species is involved in glucose deprivation-induced AMPK activity in DU145 human prostate carcinomas, and c-Jun amino-terminal kinase acts as an upstream component in AMPK activation cascades under these conditions. LKB1, which was recently identified as a direct upstream kinase of AMPK, was not detected in DU145 cells. In conclusion, our results demonstrate a novel and major role of AMPK in the post-transcriptional regulation of VEGF, further implying its potential role in tumor angiogenesis.
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PMID:Glucose deprivation increases mRNA stability of vascular endothelial growth factor through activation of AMP-activated protein kinase in DU145 prostate carcinoma. 3044 4

The molecular mechanisms driving angiogenesis in tissues derived from embryonic stem (ES) cells are currently unknown. Herein we investigated the effects of direct current (DC) electrical field treatment on endothelial cell differentiation and angiogenesis of mouse ES cells. Treatment of ES cell-derived embryoid bodies with field strengths ranging from 250 V/m to 750 V/m, applied for 60 s, dose-dependently increased the capillary area staining positive for the endothelial-specific marker platelet endothelial cell adhesion molecule-1 (PECAM-1), indicating stimulation of endothelial cell differentiation and angiogenesis. Consequently, increased expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) within 24 h was observed. Electric field treatment raised reactive oxygen species (ROS) generation for at least 48 h, which was blunted by NADPH-oxidase inhibitors diphenylen iodonium chloride (DPI) as well as 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), and increased the expression of NADPH-oxidase subunits p22-phox, p47-phox, p67-phox, and gp91-phox within 24 h. Electrical field treatment resulted in activation of extracellular regulated kinase 1,2 (ERK1,2), p38, as well as c-Jun NH2-terminal kinase (JNK). Pretreatment with the JNK inhibitor SP600125 resulted in a significant decrease in capillary areas under control conditions as well as under conditions of electrical field treatment, whereas the p38 inhibitor SB203580 was without effects. By contrast, the ERK1,2 antagonist UO126 inhibited electrical field-induced angiogenesis, whereas angiogenesis under control conditions was unimpaired. The increase in capillary areas and VEGF expression as well as activation of JNK and ERK1,2 was significantly inhibited in the presence of the free radical scavenger vitamin E underscoring the role of ROS in electrical field-induced angiogenesis of ES cells.
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PMID:Redox control of angiogenic factors and CD31-positive vessel-like structures in mouse embryonic stem cells after direct current electrical field stimulation. 1574 85

The effect of vasoactive intestinal peptide (VIP) on intracellular Ca(2+) levels and its relationship with the expression of c-fos and vascular endothelial growth factor (VEGF) as well as with neuroendocrine (NE) differentiation were investigated in human prostate LNCaP cells. VIP induced the expression of c-fos mRNA as studied by reverse transcription polymerase chain reaction (RT-PCR). It was accompanied by VIP stimulation of c-fos protein synthesis, as measured by Western blot analysis. VIP enhanced intracellular Ca(2+) levels as evaluated using the calcium probe fura-2. VIP regulation of c-fos expression depended on [Ca(2+)](i) concentration since the intracellular calcium chelator BAPTA/AM decreased c-fos expression (both mRNA and protein) to basal levels. As shown by means of real-time RT-PCR, VIP stimulated VEGF mRNA expression: the effect was inhibited by 40% in the presence of curcumin (an inhibitor of AP-1 binding), and it was dependent on Ca(2+) since BAPTA/AM inhibited this VIP action by 43%. Similar observations were made on the effects of BAPTA/AM and curcumin on VIP stimulation of VEGF protein expression. Simultaneous treatment of cells with the protein kinase A inhibitor H89 and BAPTA/AM completely blocked this VIP effect, whereas each agent alone led only to a partial inhibition. In addition, the calcium chelator blocked by 37% the ability of VIP to induce NE cell differentiation as estimated by the observation of neurite development. These features support a VIP signalling pathway that could be mediated through both cAMP and [Ca(2+)](i) increase in prostate LNCaP cancer cells. Moreover, our data suggest the implication of c-Fos on the induction of the main angiogenic factor VEGF since the promoter region of the VEGF gene possesses AP-1 (i.e., c-Fos/c-Jun heterodimer) response elements. This feature represents a link between the nuclear oncogene c-fos, angiogenesis and NE differentiation by means of an initiating signal upon VIP receptors.
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PMID:Vasoactive intestinal peptide (VIP) induces c-fos expression in LNCaP prostate cancer cells through a mechanism that involves Ca2+ signalling. Implications in angiogenesis and neuroendocrine differentiation. 1592 70

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