Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Hypoxia has a profound influence on progression and metastasis of malignant tumors. In the present report, we used the oligonucleotide microarray technique to identify new hypoxia-inducible genes in malignant melanoma with a special emphasis on angiogenesis factors. A commercially available Affymetrix gene chip system was used to analyze five melanoma cell lines of different aggressiveness. A total of 160 hypoxia-inducible genes were identified, clustering in four different functional clusters. In search of putative angiogenesis and tumor progression factors within these clusters, Cyr61, a recently discovered angiogenesis factor, was identified. Cyr61 was hypoxia-inducible in low aggressive melanoma cells; however, it showed constitutive high expression in highly aggressive melanoma cells. Further analyses of transcriptional mechanisms underlying Cyr61 gene expression under hypoxia demonstrated that an AP-1 binding motif within the Cyr61 promoter plays a central role in the hypoxic regulation of Cyr61. It could be shown by use of in vitro luciferase assays, electrophoretic mobility shift assays, and immunoprecipitation that hypoxia-inducible factor-1alpha interacts with c-Jun/AP-1 and may thereby contribute to Cyr61 transcriptional regulation under hypoxia. Taken together, the presented data show that Cyr61 is a hypoxia-inducible angiogenesis factor in malignant melanoma with tumor stage-dependent expression. This may argue for a hypoxia-induced selection process during tumor progression toward melanoma cells with constitutive high Cyr61 expression.
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PMID:Mechanisms of hypoxic gene regulation of angiogenesis factor Cyr61 in melanoma cells. 1293 82

Interleukin (IL)-8 serves as a major chemoattractant for neutrophils and has also been proposed to affect cancer progression. In the present study, we show that IGF-I stimulates IL-8 mRNA expression and IL-8 secretion in the leukemic cell line HL-60. Stimulation of IL-8 expression was completely attenuated by two inhibitors of mitogen-activated protein kinase (MAPK) kinase (MEK), which phosphorylates the MAPKs extracellular-regulated kinase (ERK)1 and ERK2, and by the c-Jun NH2-terminal kinase (JNK) inhibitor SP600125. In contrast, inhibitors of p38 MAPK and phosphatidylinositol-3 kinase (PI3K) did not abrogate the effect of IGF-I. We also show that IGF-I stimulates the activation of ERK1 and ERK2, but we could not detect any effect of IGF-I on the phosphorylation of p38, JNK(p46) or JNK(p54). Collectively, our results suggest that basal JNK activity and activation of the MEK-ERK pathway are required for upregulation of IL-8 by IGF-I in HL-60 cells.
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PMID:IGF-I stimulates IL-8 production in the promyelocytic cell line HL-60 through activation of extracellular signal-regulated protein kinase. 1457 64

Vimentin exhibits a complex pattern of developmental- and tissue-specific expression. Since it is aberrantly expressed in metastatic tumors, which have progressed through the epithelial-mesenchymal transition, it has been cited as a marker for tumor progression. Previous studies have indicated that the transcription factor activator protein (AP1) is important in tumor progression. The stable transformation of the MCF7 cell line with the oncogene c-Jun resulted in a cell line (MCF7Jun), which displayed a change in morphology, enhanced migratory and invasive properties, and metastatic behavior. Of the 21 genes whose expression levels were altered in the MCF7Jun cell line, the greatest change in expression occurred for the vimentin gene. Previously, tandem AP1 sites in the promoter were reported to be important for the serum and TPA inducibility of the vimentin gene. However, we find that the AP1 elements only contribute in part to c-Jun activation. Moreover, this activation can be duplicated in COS-1 or S2 cells by expression of c-Jun or TAM67, and is dependent only on the leucine-zipper region of c-Jun. Transient transfection analyses, electrophoretic mobility shift assays, DNA precipitation assays, and coimmunoprecipitation studies suggest that c-Jun is able to synergize with the activator protein Sp1 in binding to GC-box1 to enhance vimentin gene expression.
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PMID:c-Jun and the dominant-negative mutant, TAM67, induce vimentin gene expression by interacting with the activator Sp1. 1465 85

Osteopontin (OPN) is a multifunctional protein implicated in mammary development, neoplastic change, and metastasis. OPN is a target gene for beta-catenin-T cell factor signaling, which is commonly disturbed during mammary oncogenesis, but the understanding of OPN regulation is incomplete. Data base-assisted bioinformatic analysis of the OPN promoter region has revealed the presence of T cell factor-, Ets-, and AP-1-binding motifs. Here we report that beta-catenin, Lef-1, Ets transcription factors, and the AP-1 protein c-Jun each weakly enhanced luciferase expression from a OPN promoter-luciferase reporter construct, transiently transfected into a rat mammary cell line. OPN promoter responsiveness to beta-catenin and Lef-1, however, was considerably enhanced by Ets transcription factors including Ets-1, Ets-2, ERM, and particularly PEA3. PEA3 also enhanced promoter responsiveness to the AP-1 protein c-Jun. Co-transfection of cells with beta-catenin, Lef-1, PEA3, and c-Jun in combination increased luciferase expression by up to 280-fold and induced expression of endogenous rat OPN. In six human breast cell lines, those that highly expressed OPN also expressed PEA3 and Ets-1. Moreover, there was a significant association of immunocytochemical staining for OPN and one of beta-catenin, Ets-1, Ets-2, PEA3, or c-Jun, in the 29 human breast carcinomas tested. This study shows that beta-catenin/Lef-1, Ets, and AP-1 transcription factors can cooperate in a rat mammary cell line in stimulating transcription of OPN and that their independent presence is associated with that of OPN in a group of human breast cancers. These results suggest that the presence of these transcription factors in human breast cancer is responsible in part for the overexpression of OPN that, in turn, is implicated in mammary neoplastic progression and metastasis.
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PMID:Ets gene PEA3 cooperates with beta-catenin-Lef-1 and c-Jun in regulation of osteopontin transcription. 1499 May 65

Activation of the transcription factor AP-1 (activator protein-1) is required for tumor promotion and maintenance of malignant phenotype. A number of AP-1-regulated genes that play a role in tumor progression have been identified. However, AP-1-regulated genes driving tumor induction are yet to be defined. Previous studies have established that expression of a dominant-negative c-Jun (TAM67) inhibits phorbol 12-tetradecanoyl-13-acetate (TPA)-induced AP-1 transactivation as well as transformation in mouse epidermal JB6/P+ cells and tumor promotion in mouse skin carcinogenesis. In this study, we utilized the tumor promotion-sensitive JB6/P+ cells to identify AP-1-regulated TAM67 target genes and to establish causal significance in transformation for one target gene. A 2700 cDNA microarray was queried with RNA from TPA-treated P+ cells with or without TAM67 expression. Under conditions in which TAM expression inhibited TPA-induced transformation, microarray analysis identified a subset of six genes induced by TPA and suppressed by TAM67. One of the identified genes, the high-mobility group protein A1 (Hmga1) is induced by TPA in P+, but not in transformation-resistant P cells. We show that TPA induction of the architectural transcription factor HMGA1 is inhibited by TAM67, is extracellular-signal-regulated kinase (ERK)-activation dependent, and is mediated by AP-1. HMGA1 antisense construct transfected into P+ cells blocked HMGA1 protein expression and inhibited TPA-induced transformation indicating that HMGA1 is required for transformation. HMGA1 is not however sufficient as HMGA1a or HMGA1b overexpression did not confer transformation sensitivity on P- cells. Although HMGA1 expression is ERK dependent, it is not the only ERK-dependent event required for transformation because it does not suffice to rescue ERK-deficient P- cells. Our study shows (a) TAM 67 when it inhibits AP-1 and transformation, targets a relatively small number of genes; (b) HMGA1, a TAM67 target gene, is causally related to transformation and therefore a potentially important target for cancer prevention.
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PMID:Dominant-negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation. 1506 52

Although elevated expression and increased tyrosine phosphorylation of focal adhesion kinase (FAK) are crucial for tumor progression, the mechanism by which FAK promotes oncogenic transformation is unclear. We have therefore determined the role of FAK phosphorylation at tyrosine 861 in the oncogenic transformation of NIH3T3 fibroblasts. FAK phosphorylation at tyrosine 861 was increased in both constitutively H-Ras-transformed and H-Ras-inducible NIH3T3 cells, in parallel with cell transformation. However, H-Ras-inducible cells transfected with the nonphosphorylatable mutant FAK Y861F showed decreased migration/invasion, focus forming activity and anchorage-independent growth, compared with either wild-type or kinase-defective FAK. In contrast to unaltered FAK/Src activity, the association of FAK and p130(CAS) was decreased in FAK Y861F-transfected cells, and FAK phosphorylation at tyrosine 861 enhanced this association in vitro. Consistently, FAK Y861F-transfected cells were defective in activation of c-Jun NH(2)-terminal kinase and in expression of matrix metalloproteinase-9 during transformation. Taken together, these results strongly suggest that FAK phosphorylation at tyrosine 861 is crucial for H-Ras-induced transformation through regulation of the association of FAK with p130(CAS).
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PMID:Phosphorylation of focal adhesion kinase at tyrosine 861 is crucial for Ras transformation of fibroblasts. 1512 32

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

The importance of prolactin (PRL) in physiological proliferation and differentiation of the mammary gland, together with high levels of PRL receptors in breast tumors, the association of circulating PRL with incidence of breast cancer, and the recognition of locally produced PRL, point to the need for greater understanding of PRL actions in mammary disease. Although PRL has been shown to activate multiple kinase cascades in various target cells, relatively little is known of its signaling pathways in the mammary gland apart from the Janus kinase 2/ signal transducer and activator of transcription 5 pathway, particularly in tumor cells. Another potential effector is activating protein-1 (AP-1), a transcription complex that regulates processes essential for neoplastic progression, including proliferation, survival and invasion. We demonstrate that PRL activates AP-1 in MCF-7 cells, detectable at 4 h and sustained for at least 24 h. Although Janus kinase 2 and ERK1/2 are the primary mediators of PRL-induced signals, c-Src, phosphatidylinositol 3'-kinase, protein kinase C, and other MAPKs contribute to maximal activity. PRL activation of these pathways leads to increased c-Jun protein and phosphorylation, JunB protein, and phosphorylation of c-Fos, elevating the levels of AP-1 complexes able to bind DNA. These active AP-1 dimers may direct expression of multiple target genes, mediating some of PRL's actions in mammary disease.
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PMID:Multiple kinase cascades mediate prolactin signals to activating protein-1 in breast cancer cells. 1531 52

Cancer progression depends on an accumulation of metastasis-supporting cell signaling molecules, which target signal transduction pathways and, ultimately, gene expression. One such molecule, osteopontin (OPN), represents a key molecular signaling event in tumor progression and metastasis. However, the transcriptional regulatory mechanisms that underlie OPN expression in the setting of breast cancer have not been well studied. In this regard, we have examined the differential transcriptional regulation of OPN in the murine mammary epithelial tumor cell lines, 4T1 and 4T07, which are sublines derived from the parental population of 410.4 cells from Balb/cfC3H mice. These lines are phenotypically heterogeneous in their metastatic behavior. 4T1 hematogenously metastasizes to the lung, liver, bone, and brain, whereas 4T07 is highly tumorigenic but fails to metastasize. The tumor growth and metastatic spread of 4T1 cells closely mimics stage IV breast cancer. We demonstrate that a Ras-independent, phosphoinositide-3 kinase-dependent, c-Jun N-terminal kinase-dependent phosphorylation of c-Jun results in binding of an AP-1 c-Jun homodimer to the OPN promoter in 4T1 cells. This differential up-regulation of OPN gene transcription and protein expression in 4T1 cells conveys in vitro correlates of a metastatic phenotype. These results provide new insight into the transcriptional regulation of OPN as a key mediator of metastatic behavior in malignancy.
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PMID:Differential osteopontin expression in phenotypically distinct subclones of murine breast cancer cells mediates metastatic behavior. 1534 45

Exposure to cigarette smoke (CS) can lead to the development of lung cancer, but the molecular mechanisms underlying this process remain unclear. Given that activator protein 1 (AP-1) regulates genes involved in both physiologic and pathophysiologic processes, we have investigated the effects of CS on Jun and Fos family member expression and regulation using a nonmalignant human bronchial epithelial cell line, 1HAEo. Exposure to CS caused a marked upregulation of c-Jun, c-Fos, and Fra-1, but not of Fra-2, Jun-B, and Jun-D expression. Because Fra-1 is overexpressed in various tumors and upregulates genes associated with tumor progression, we further elucidated the mechanisms that control CS-stimulated fra-1 induction. CS stimulated fra-1 induction primarily at the transcriptional level. However, epidermal growth factor receptor (EGFR)-specific inhibitor, AG1478, completely suppressed CS-stimulated fra-1 expression. Similarly, the specific inhibitors of extracellular signal-regulated kinase (ERK), c-Jun NH2 terminal kinase (JNK), and p38 kinase signaling markedly suppressed fra-1 induction. Consistent with this finding, AG1478 blocked CS-stimulated ERK, JNK, and p38 phosphorylation. These results suggest that EGFR-activated multiple kinase signaling is essential for fra-1 induction. Furthermore, treatment of cells with GM6001, which inhibits matrix metalloproteinase activity, significantly suppressed CS-stimulated EGF shedding, EGFR and ERK kinase phosphorylation, and subsequent fra-1 induction. Collectively, our findings indicate an obligatory role for metalloproteinase-EGFR-mediated mitogen-activated protein kinase signaling in controlling CS-induced fra-1 expression.
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PMID:Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells. 1552 91


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