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)

Phosphorylation on serine or threonine residue preceding proline (Ser/Thr-Pro) is a key regulatory mechanism. The conformation of certain phosphorylated Ser/Thr-Pro bonds is regulated specifically by the prolyl isomerase Pin1. It has been reported that Pin1 is strikingly overexpressed in a subset of human tumors. A differential-display screen reveals that Pin1 increases the transcription of several beta-catenin target genes, including those encoding cyclin D1 and c-Myc. Pin1 cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1. We have previously reported that Pin1 is overexpressed in oral squamous cell carcinoma (OSCC) and its level correlates with Cyclin D1 expression. However, the analysis of the relationship between Pin1 and other cyclin genes has not been demonstrated in human OSCC. We examined Pin1 mRNA and protein expressions in OSCC cell lines, and analyzed Pin1/cyclins expression by RT-PCR. We report that Pin1 mRNA correlates with Cyclin D1 mRNA expression and the expression of many cyclin genes is associated with lymph node metastasis in OSCC. These results indicate that Pin1 is a regulator of Cyclin D1 expression in OSCC and might have a role in oncogenesis; and the expression of many cyclin genes will be an indicator of lymph node metastasis in OSCC.
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PMID:Expression status of Pin1 and cyclins in oral squamous cell carcinoma: Pin1 correlates with Cyclin D1 mRNA expression and clinical significance of cyclins. 1279 68

Human 12(S)-lipoxygenase is a platelet-type 12(S)-lipoxyenase. Its expression is detected in human erythroleukemia cells, human skin epidermal cells and human epidermoid carcinoma A431 cells. Treatment of A431 cells with EGF or PMA induces the gene expression of human 12(S)-lipoxygenase. The induction of gene expression is mediated through the cell signaling of MAPK activation, followed by the induction of c-Jun expression. The transcription factor Sp1 binding to the two Sp1 recognition motifs residing at -158 to 150 bp and -123 to 114 bp in the gene promoter is found to be essential for both EGF- and PMA-induced gene expression of human 12(S)-lipoxygenase. However, no change of Sp1 binding to GC-rich sequence was observed while no AP-1-binding site can be found in the responsive region of the promoter in EGF- and PMA-induced promoter activation of the human 12(S)-lipoxygenase gene. Since both of the transcription factors c-Jun and Sp1 are prerequisite for EGF and PMA response, interaction between c-Jun and Sp1 may account for the functional regulation of human 12(S)-lipoxygenase gene regulation. The direct and cooperative interaction between c-Jun and Sp1 induced by EGF or PMA activates the expression of the human 12(S)-lipoxygenase gene. Therefore, Sp1 may serve at least in part as a carrier to bring c-Jun to the promoter, thu's transactivating the transcriptional activity of the human 12(S)-lipoxygenase gene.
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PMID:Cell signaling and gene regulation of human 12(S)-lipoxygenase expression. 1451 67

The anticancer effects of retinoids are mainly mediated by their nuclear receptors. Recent studies have demonstrated that retinoic acid receptor beta (RARbeta) plays a pivotal role from the early stages of laryngeal carcinogenesis; however, the exact mechanism of this detrimental effect has not yet been elucidated. One of the best-documented actions of retinoid receptors is the transrepression of activator protein-1 (AP-1) transcription factor activity, although this complex interplay has not been clarified. The present report is the first systematic morphological evaluation of the cross-talk of RARbeta and AP-1 transcription factor in a large series of human laryngeal tissues containing normal epithelium, premalignant lesions (hyperplasia and/or dysplasia) and squamous cell carcinoma. Immunohistochemical methodology was performed on formalin-fixed, paraffin-embedded sections by using a panel of monoclonal and polyclonal antibodies against RARbeta and the AP-1 components c-Jun, p-c-Jun (phosphorylated, active c-Jun) and c-Fos proteins. Their expression was screened and compared in 154 patients with various laryngeal histological entities. Nuclear expression of RARbeta, c-Jun, p-c-Jun and c-Fos was detected in 81 (89.2%), 48 (52.8%), 66 (72.6%) and 73 (80.3%), respectively, out of 91 specimens with normal-appearing laryngeal epithelium; in 86 (87.8%), 94 (95.9%), 94 (95.9%) and 94 (95.9%), respectively, out of 98 specimens with hyperplastic laryngeal epithelium; in 58 (56.8%), 92 (90.2%), 96 (94.1%) and 96 (94.1%), respectively, out of 102 specimens with dysplastic laryngeal epithelium; in 10 (22.3%), 41 (91.2%), 44 (97.8%) and 41 (91.2%), respectively, out of 45 specimens with well-differentiated squamous cell carcinoma; in 13 (30.3%), 37 (86%), 39 (90.7%) and 41 (95.3%), respectively, out of 43 specimens with moderately-differentiated squamous cell carcinoma; and in 8 (66.7%), 10 (83.3%), 12 (100%) and 12 (100%), respectively, out of 12 specimens with poorly-differentiated squamous cell laryngeal carcinoma. Statistical analysis and correlation of the intensity of nuclear immunostaining of the studied proteins among the various histological entities revealed statistically significant results. The progressive upregulation of the AP-1 transcription factor constituents and downregulation of the RARbeta protein detected from the onset of laryngeal tumorigenesis suggests an important role for the immediate-early AP-1/RARbeta on/off "switch" in the process of laryngeal carcinogenesis.
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PMID:Differential expression of retinoic acid receptor beta (RARbeta) and the AP-1 transcription factor in normal, premalignant and malignant human laryngeal tissues. 1501 78

Retinoids have shown clinical efficacy in cancer chemoprevention and therapy presumably by modulating the growth, differentiation, and apoptosis of normal, premalignant, and malignant cells. To better understand the mechanisms by which retinoids exert their effects, we used a high-throughput Western blotting method (Becton-Dickinson PowerBlot) to evaluate changes in the levels of cellular signaling proteins in head and neck squamous cell carcinoma cells treated with the cytostatic all-trans-retinoic acid or with the proapoptotic retinoids 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid or N-(4-hydroxyphenyl)retinamide. Treatments of the head and neck squamous cell carcinoma cells with these retinoids for 24 h resulted in increased levels of 14, 22, and 22 proteins and decreased levels of 5, 10, and 7 proteins, respectively. The changes in the levels of the following proteins were confirmed by conventional western immunoblotting: all-trans-retinoic acid increased ELF3, topoisomerase II alpha, RB2/p130, RIG-G, and EMAPII and decreased MEF2D and cathepsin L. N-(4-Hydroxyphenyl)retinamide up-regulated ELF3, c-Jun, Rb2/p130, JAK1, p67phox, Grb2, O(6)-methylguanine-DNA methyltransferase, and Ercc-1. 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid increased Rb2/p130, c-Jun, Sp1, Sin, and tomosyn and decreased cathepsin L, Mre11, and topoisomerase II alpha. Some of these proteins were also modulated by these retinoids in other human cancer cell lines. A subset of the proteins were modulated similarly by the different retinoids, whereas changes in other proteins were unique for each retinoid. These results suggest that the mechanisms by which these retinoids modulate proteins are distinct but may overlap. Some of the retinoid-modulated proteins identified in this study may be novel candidates for mediating different responses to retinoids.
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PMID:Identification of retinoid-modulated proteins in squamous carcinoma cells using high-throughput immunoblotting. 1505 97

The mitogen activated serine/threonine kinases (MAPKs) constitute extracellular signal-regulated protein kinases (ERKs), c-Jun N-terminal kinases (JNKs) and p38 MAPK, with an important role in cell proliferation and transformation. Earlier studies from our laboratory had indicated a role for MAPK pathway in oral cancer. Our current study was aimed at examining the role of a MAPK-ERK3, in chewing-tobacco associated oral squamous cell carcinoma. We constructed a cDNA library from primary oral cancer tissue, cloned and isolated the ERK3 gene. The gene was sequenced and the sequence submitted to GenBank (Accession number AF420474). The oral cancer ERK3 clone demonstrated 100% homology to human ERK3 isolated from fetal skeletal muscle, with four specific nucleotide alterations in the non-coding region of the gene, comprising deletion of 'TTT' between 2701 and 2705 nt; 'G' to 'T' substitution at 188 nt; insertion of 'A' between 121 and 122 nt, and insertion of 'CTTTA' between 3391 and 3392 nt. Southern analysis of EcoRI genomic digests indicated ERK3 specific fragments of 11, 8.6, 6.5 and 3.2 kb sizes. The mRNA transcript analysis defined a single transcript of 4.5 kb. RT-PCR analysis revealed a three- to eight-fold increase in ERK3 expression in a majority (90%) of oral cancer tissues and peripheral blood cells (61.5%) of the patients, whereas absence or low levels of expression was observed in peripheral blood cells of 74% clinically normal healthy individuals with no tobacco habits, and overexpression in PBC from 26% normal individuals. The alterations in the non-coding region of ERK3 gene cloned from oral cancer tissue, may affect stability or regulation of mRNA, resulting in overexpression in the patient samples. The overexpression of the gene in the normal healthy individuals may be indicative of increased risk of developing oral cancers in this group.
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PMID:Molecular cloning, isolation and characterisation of ERK3 gene from chewing-tobacco induced oral squamous cell carcinoma. 1517 40

Cyclooxygenase-2 (COX-2) is an inducible enzyme responsible for high-level prostaglandin production during inflammation and carcinogenesis. In this study, the transcriptional regulation of COX-2 expression induced by epidermal growth factor (EGF) in human epidermoid carcinoma A431 cells was studied. EGF treatment induced the expression of COX-2 mRNA, protein, promoter and enzyme activity in a time-dependent manner. EGF-induced COX-2 promoter activity was inhibited by overexpression of the dominant-negative forms of Ras and ERK2. Induction of COX-2 and c-Jun by EGF was completely suppressed by MEK inhibitor combined with JNK inhibitor. Analysis of the COX-2 promoter binding proteins by gel mobility shift assay and DNA affinity precipitation assay revealed that c-Jun and p300 binding to CRE/E-box site were responsible for the EGF-induced COX-2 gene transcription. Overexpression of p300 significantly enhanced COX-2 promoter activity in cells overexpressed of c-Jun or treated with EGF. EGF- and c-Jun-induced transcription of COX-2 promoter was repressed by cotransfection of E1A in a dose-dependent manner. All together, these results indicated that the EGF-induced expression of COX-2 in A431 cells was mediated through the Ras-ERK/JNK signaling pathway, and subsequent induction of c-Jun following MAPK activation, in cooperation with coactivator p300, was required for the EGF response.
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PMID:Essential role of c-Jun induction and coactivator p300 in epidermal growth factor-induced gene expression of cyclooxygenase-2 in human epidermoid carcinoma A431 cells. 1523 18

The signal transduction of human 12(S)-lipoxygenase and the regulation of gene activation, induced by epidermal growth factor (EGF), are discussed in this review article. Treatment of human epidermoid carcinoma A431 cells with EGF induces the gene expression of human 12(S)-lipoxygenase, and two Sp1 binding sites residing at -158 to -150 bp and -123 to -114 bp are essential in the mediation of EGF induction of the 12(S)-lipoxygenase gene. EGF induces MAPK activation in cells, followed by the activation of AP1. Thus, the biosynthesis of c-Jun is enhanced, which subsequently interacts with Sp1. c-Jun on Sp1/c-Jun complex is then recruited to gene promoter through the binding of Sp1 to Sp1-binding sites on gene promoter. Subsequent transactivation of the promoter activation of the human 12(S)-lipoxygenase gene is induced. In addition to the functional role of Sp1 in gene regulation of 12(S)-lipoxygenase, recent studies have also demonstrated that Sp1 acting as an anchor protein to recruit transcription factor c-Jun is essential for growth factor and/or phorbol ester-induced expression of several genes.
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PMID:Transcription factor Sp1 functions as an anchor protein in gene transcription of human 12(S)-lipoxygenase. 1612

Our laboratory has used a rodent model of human esophageal squamous cell carcinoma to identify putative chemopreventive agents for this disease and to determine their mechanisms of action. In the present study, we treated F344 rats with the esophageal carcinogen, N-nitrosomethylbenzylamine (NMBA), thrice per week for 5 weeks. Beginning 1 week later, they were fed a synthetic diet containing 5% black raspberries (BRB) for the duration of the bioassay (25 weeks). Rats were sacrificed at weeks 9, 15, and 25. Esophageal tissues were collected, and tumor data were recorded. The expression and enzymatic activities of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as the expression of c-Jun in the esophagi, were evaluated to investigate the mechanism(s) by which black raspberries modulate tumorigenesis. At week 25, BRB inhibited tumor multiplicity, the standard end point in this tumor model, from 3.78 +/- 0.41 tumors per rat in NMBA-treated animals to 2.23 +/- 0.21 tumors per rat in animals treated with NMBA plus BRB (P < 0.005). BRB reduced mRNA and protein expression levels of COX-2, iNOS, and c-Jun as well as the level of prostaglandin E(2) in preneoplastic lesions of the esophagus at week 25. The berries inhibited mRNA expression of iNOS and c-Jun, but not COX-2, in papillomatous lesions of the esophagus. Prostaglandin E(2) and total nitrite levels were also decreased by BRB in papillomas. These results suggest a novel tumor suppressive role of BRB through inhibition of COX-2, iNOS, and c-Jun.
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PMID:Chemopreventive properties of black raspberries in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis: down-regulation of cyclooxygenase-2, inducible nitric oxide synthase, and c-Jun. 1651 Jun 8

Angiogenesis, the formation of new blood vessels, is critical to tumor growth and metastasis. Vascular endothelial growth factor (VEGF), an important angiogenic activator, is essential for angiogenesis. Our laboratory has used a rodent model of human esophageal squamous cell carcinoma (ESCC) to identify putative chemopreventive agents for this disease and determine their mechanisms of action. We reported that dietary black raspberry powder (BRB) inhibits N-nitrosomethylbenzylamine (NMBA)-induced tumor development in the rat esophagus by inhibiting the formation of DNA adducts and reducing the proliferation rate of preneoplastic cells. On a molecular level, BRB downregulates the expression of c-Jun, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). In this study we analyzed the effect of BRB on angiogenesis. VEGF expression was determined by real-time RT-PCR and immunohistochemical analysis of microvessel density (MVD). BRB significantly suppressed VEGF-C expression from a 2.38 (+/- 0.34)-fold increase in animals treated with NMBA alone to a 1.08 (+/- 0.22)-fold increase in animals treated with NMBA plus BRB (P < 0.005). The MVD of esophagus was decreased from 53.7 +/- 5.6 vessels/cm in animals treated with NMBA alone to 22.6 +/- 2.6 vessels/cm in animals treated with NMBA plus BRB (P < 0.0001). Our data also suggest that downregulation of VEGF is correlated with suppression of COX-2 (r2 = 0.86, P < 0.001) and iNOS (r2 = 0.81, P < 0.005). As high vascularity is a risk factor for metastasis and tumor recurrence, BRB may have cancer therapeutic effects in human esophageal cancer.
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PMID:Black raspberries inhibit N-nitrosomethylbenzylamine (NMBA)-induced angiogenesis in rat esophagus parallel to the suppression of COX-2 and iNOS. 1677 90

Squamous cell carcinoma (SCC) is an invasive malignancy of epidermal keratinocytes. Surgical excision is currently the main treatment; however, this can cause scarring and disfigurement. There is accordingly, an acute need for alternative strategies to treat SCC. The transcription factor c-Jun is expressed in human SCC and another common form of invasive skin cancer, basal cell carcinoma together with the mitogenic marker-proliferating cell nuclear antigen. Here, we have employed DNAzymes (catalytic DNA molecules) targeting c-Jun (Dz13) to inhibit c-Jun expression in SCC cells. Dz13 inhibits SCC proliferation and suppresses solid SCC tumor growth and tumor angiogenesis in severe combined immunodeficient mice. We further demonstrate that Dz13 inhibits c-Jun, together with matrix metalloproteinase (MMP)-2 and MMP-9 expression in the tumors, consistent with DNAzyme inhibition of MMP-2 and MMP-9 gelatinolytic activity by zymography. Dz13 also suppressed the expression of vascular endothelial growth factor and fibroblast growth factor-2 in the tumors. These findings demonstrate that c-Jun regulates SCC growth and suggest that DNAzymes targeting this transcription factor may potentially be useful as inhibitors of cutaneous carcinoma.
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PMID:Squamous cell carcinoma growth in mice and in culture is regulated by c-Jun and its control of matrix metalloproteinase-2 and -9 expression. 1678 94


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