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)

Efforts have been made to develop a chemoprevention strategy that selectively triggers apoptosis in malignant cancer cells. Previous studies showed that capsaicin, the major pungent ingredient of red pepper, had differential effect between normal and transformed cells. As an approach to unveil the molecular mechanism by which capsaicin selectively induces apoptosis in transformed cells, we investigated the effect of capsaicin in nontransformed and ras-transformed cells of a common origin: parental (MCF10A) and H-ras-transformed (H-ras MCF10A) human breast epithelial cells. Here, we show that capsaicin selectively induces apoptosis in H-ras-transformed cells but not in their normal cell counterparts. The capsaicin-induced apoptosis, which is dependent on ras transformation, involves the activity of DEVDase (caspase-3 like). In H-ras MCF10A cells, capsaicin treatment markedly activated c-Jun N-terminal protein kinase (JNK)-1 and p38 matigen-activated protein kinase (MAPK) while it deactivated extracellular signal-regulated protein kinases (ERKs). The use of kinase inhibitors and overexpression of dominant-negative forms of MAPKs demonstrated a role of JNK-1 and p38, but not that of ERKs, in apoptosis induced by capsaicin in H-ras-transformed MCF10A cells. Based on the present study, we propose that capsaicin selectively induces apoptosis through modulation of ras-downstream signaling molecules in ras-activated MCF10A cells. Taken in conjunction with the fact that uncontrolled ras activation is probably the most common genetic defect in human cancer cells, our finding may be critical to the chemopreventive potential of capsaicin and for developing a strategy to induce tumor cell-specific apoptosis.
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PMID:Roles of JNK-1 and p38 in selective induction of apoptosis by capsaicin in ras-transformed human breast epithelial cells. 1247 62

To study the signaling pathway involved in the regulation of galectin-3 expression we used phorbol ester to stimulate macrophage differentiation of THP-1 cells. Treatment with phorbol 12-myristate 13-acetate (PMA) increased significantly the level of expression of galectin-3 in THP-1 cells. PMA-induced galectin-3 overexpression was blocked by: protein kinase C inhibitors staurosporine, calphostin C, and apigenin; tyrosine-specific protein kinase inhibitors genistein and tyrphostin A25; PD 98059, a selective inhibitor of mitogen-activated protein kinase (MAPK) kinase 1 (MEK1 or MKK1); and SB 203580, a specific inhibitor of p38 MAPK. Galectin-3 up-regulation was not affected by exposure to two inhibitors of cAMP-dependent protein kinase (PKA), H-89 and KT5720. Co-transfection of pPG3.5, a plasmid vector containing the rabbit galectin-3 promoter and the constructs pMCL-MKK1 N3 or pRC-RSV-MKK3Glu that constitutively express MKK1 and MKK3, raised the activity of galectin-3 promoter by 185% and 110%, respectively. Co-transfection with a Ha-Ras expression vector stimulated galectin-3 promoter activity approximately 10-fold. Expression of c-Jun or v-Jun raised the level of galectin-3 promoter activity more the three- and fourfold, respectively. Co-transfection of c-Jun and pPG3.5 5'-upstream deletion mutants resulted in a reduction of the galectin-3 promoter activity by 50% to 80%. Transfection of c-Jun, v-Jun or Ha-Ras increased significantly galectin-3 protein in THP-1 cells. These findings indicated that Ras/MEKK1/MKK1-dependent/AP-1 signal transduction pathway plays an important role in the expression of galectin-3 in PMA-stimulated macrophages. We further investigated the effect of modified lipoproteins on galectin-3 expression in macrophages. Murine resident peritoneal macrophages loaded with acetylated low-density lipoprotein (AcLDL) or oxidized LDL (OxLDL) showed increased galectin-3 protein and mRNA. These results showed that treatment of macrophages with PMA or modified lipoproteins results in galectin-3 overexpression. These findings may explain the enhanced expression of galectin-3 in atherosclerotic foam cells and suggest that Ras/MAPK signal transduction pathway is involved in controlling this gene.
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PMID:Galectin-3 expression in macrophages is signaled by Ras/MAP kinase pathway and up-regulated by modified lipoproteins. 1278 25

This study characterizes 3 cases of mesenchymal chondrosarcoma (MC) utilizing a proteomic approach that allows for the detection, visual quantification, cellular compartmentalization, and assessment of the functional state of certain proteins that may promote tumor growth and/or oppose apoptosis. Immunohistochemical procedures were performed to detect the following protein antigens: CD99, interleukin (IL)-1alpha, IL-6, transforming growth factor (TGF)-alpha, conventional (c) protein kinase C (cPKC)-alpha, cPKC-betaII, phosphorylated (p)-PKC-alpha/betaII, c-kit (CD117), platelet-derived growth factor receptor (PDGFR)-alpha, PDGFR-beta, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)-2/neu, cathepsin D, angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) receptor, p21ras, the alpha subunit of farnesyl and geranylgeranyl transferase (FTalpha/GGTalpha), phospho (p)-c-Jun N-terminal kinase (p-JNK), p-p38 mitogen-activated protein kinase (MAPK), cyclin D1, c-Jun, Ki-67, bcl-2, TGF-beta1 latency-associated peptide (LAP), TGF-betaRII, and cyclooxygenase (COX)-2. Immunoreactivities were scored from 0 to 3+ positivity using bright-field microscopy. The results showed that malignant mesenchymal chondroblasts exhibit stronger expressions of CD99, IL-1alpha, cPKC-alpha, p-PKC-alpha/betaII, PDGFR-alpha, p-JNK, Ki-67, and bcl-2 antigens than their more mature-appearing chondrocytic counterparts in MC. In conclusion, molecular profiling of mesenchymal chondrosarcoma using a proteomic approach characterized the mesenchymal chondroblasts as possessing pathways that incorporate PKC-alpha and PDGFR-alpha signaling and anti-apoptotic bcl-2 expression. Specific therapies to target the mesenchymal chondroblasts in mesenchymal chondrosarcoma might include interferon-alpha, rapamycin, ciprofloxacin, and STI571.
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PMID:Mesenchymal chondrosarcoma: molecular characterization by a proteomic approach, with morphogenic and therapeutic implications. 1281 16

Transforming growth factor (TGF)-beta1 acts as a potent growth inhibitor of prostate epithelial cells, and aberrant function of its receptor type I and II correlates with tumor aggressiveness. However, intracellular and serum TGF-beta1 levels are elevated in prostate cancer patients and further increased in patients with metastatic carcinoma, suggesting the oncogenic switch of TGF-beta1 role in prostate tumorigenesis. Recently, we reported the mitogenic conversion of TGF-beta1 effect by oncogenic Ha-Ras in prostate cancer cells. Here, we show that TGF-beta1 activates interleukin (IL)-6, which has been implicated in the malignant progression of prostate cancers, via multiple signaling pathways including Smad2, nuclear factor-kappaB (NF-kappaB), JNK, and Ras. TGF-beta1-induced IL-6 gene expression was strongly inhibited by DN-Smad2 but not by DN-Smad3 while it was further activated by wild-type Smad2 transfection. IL-6 activation by TGF-beta1 was accompanied by nuclear translocation of NF-kappaB, which was blocked by the p38 inhibitors SB202190 and SB203580 or by IkappaBalphaDeltaN transfection, indicating the crucial role for the p38-NF-kappaB signaling in TGF-beta1 induction of IL-6. TGF-beta1 activated c-Jun phosphorylation, and IL-6 induction by TGF-beta1 was severely impeded by DN-c-Jun and DN-JNK or AP-1 inhibitor curcumin, showing that the JNK-c-Jun-AP-1 signaling plays a pivotal role in TGF-beta1 stimulation of IL-6. It was also found that the Ras-Raf-MEK1 cascade is activated by TGF-beta1 and participates in the TGF-beta1 induction of IL-6 in an AP-1-dependent manner. Cotransfection assays demonstrated that TGF-beta1 stimulation of IL-6 results from the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK-c-Jun-AP-1, or Ras-Raf-MEK1 cascades. In addition, a time course IL-6 decay revealed that mRNA stability of IL-6 is modestly increased by TGF-beta1, indicating that TGF-beta1 also regulates IL-6 at the post-transcriptional level. Intriguingly, IL-6 inactivation restored the sensitivity to TGF-beta1-mediated growth arrest and apoptosis, suggesting that elevated IL-6 in advanced prostate tumors might act as a resistance factor against TGF-beta1. Collectively, our data demonstrate that IL-6 expression is stimulated by tumor-producing TGF-beta1 in human prostate cancer cells through multiple signaling pathways including Smad2, p38, JNK, and Ras, and enhanced expression of IL-6 could contribute to the oncogenic switch of TGF-beta1 role for prostate tumorigenesis, in part by counteracting its growth suppression function.
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PMID:Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. 1285 69

Ras expression has been suggested as a marker for tumor aggressiveness of breast cancer,including the degrees of invasion and tumor recurrence.We showed previously that H-ras, but not N-ras, up-regulates matrix metalloproteinase 2 expression and induces invasive phenotype in MCF10A human breast epithelial cells (A. Moon, et al. Int. J. Cancer, 85: 176-181, 2000). In this study, we show that H-ras also promotes cell motility more effectively than N-ras in MCF10A cells. We have investigated H-ras-specific signaling pathway(s) critical for H-ras-mediated cell motility and invasive phenotype. Whereas neither H-ras nor N-ras activated c-Jun NH(2)-terminal kinase 1, both H-ras and N-ras effectively activated extracellular signal-regulated protein kinase (ERK) -1,2. Importantly, prominent activation of p38 mitogen-activated protein kinase was shown only in H-ras-activated cells but not in N-ras-activated MCF10A cells. Functional significance of H-ras-activated p38 in invasiveness and cell motility was evidenced by studies using SB203580, a chemical inhibitor of p38, and a dominant-negative construct of p38. Whereas inhibition of c-Jun NH(2)-terminal kinase 1 activity had no effect on H-ras-induced MCF10A cell invasion and motility, the inhibition of the ERK pathway using a chemical inhibitor PD98059 or dominant-negative mutant of mitogen-activated protein/ERK kinase 1, an activator of ERKs, significantly reduced H-ras-induced invasion and migration. We also provide evidence that p38 and, to a lesser degree, ERKs, are critical for H-ras-mediated up-regulation of matrix metalloproteinase 2. Taken together, the present study shows that H-ras activation of both p38 and ERKs induces cell invasion and motility, whereas N-ras activation of ERKs alone is not sufficient. This study reveals the p38 kinase as a key signaling molecule differentially regulated by H-ras and N-ras, leading to H-ras-specific cell invasive and migrative phenotypes in human breast epithelial cells.
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PMID:p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells. 1450 Mar 81

Dmp1 prevents tumor formation by activating the Arf-p53 pathway. In cultured primary cells, the Dmp1 promoter was efficiently activated by oncogenic Ha-Ras(V12), but not by overexpressed c-Myc or E2F-1. Dmp1 promoter activation by Ras(V12) depended on Raf-MEK-ERK signaling. Induction of p19(Arf) and p21(Cip1) by oncogenic Raf was compromised in Dmp1-null cells, which were resistant to Raf-mediated premature senescence. A Ras(V12)-responsive element was mapped to the 5' leader sequence of the murine Dmp1 promoter, where endogenous Fos and Jun family proteins bind. Dmp1 promoter activation by Ras(V12) was strikingly impaired in c-Jun as well as in JunB knock-down cells, suggesting the critical role of Jun proteins in the activation of the Dmp1 promoter. A Ras(V12)-responsive element was mapped to the unique Dmp1/Ets site on the Arf promoter, where endogenous Dmp1 proteins bind upon oncogenic Raf activation. Therefore, activation of Arf by Ras/Raf signaling is indirectly mediated by Dmp1, explaining why Dmp1-null primary cells are highly susceptible to Ras-induced transformation. Our data indicate the presence of the novel Jun-Dmp1 pathway that directly links oncogenic Ras-Raf signaling and p19(Arf), independent of the classical cyclin D1/Cdk4-Rb-E2F pathway.
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PMID:Ras-Raf-Arf signaling critically depends on the Dmp1 transcription factor. 1560 44

The inducible transcriptional complex AP-1, composed of c-Fos and c-Jun proteins, is crucial for cell adaptation to many environmental changes. While its mechanisms of activation have been extensively studied, how its activity is restrained is poorly understood. We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers. Using nonsumoylatable mutants of c-Fos and c-Jun as well as a chimeric protein mimicking sumoylated c-Fos, we show that sumoylation entails lower AP-1 transactivation activity. Interestingly, single sumoylation at any of the three acceptor sites of the c-Fos/c-Jun dimer is sufficient to substantially reduce transcription activation. The lower activity of sumoylated c-Fos is not due to inhibition of protein entry into the nucleus, accelerated turnover, and intrinsic inability to dimerize or to bind to DNA. Instead, cell fractionation experiments suggest that decreased transcriptional activity of sumoylated c-Fos is associated with specific intranuclear distribution. Interestingly, the phosphorylation of threonine 232 observed upon expression of oncogenically activated Ha-Ras is known to superactivate c-Fos transcriptional activity. We show here that it also inhibits c-Fos sumoylation, revealing a functional antagonism between two posttranslational modifications, each occurring within a different moiety of a bipartite transactivation domain of c-Fos. Finally we report that the sumoylation of c-Fos is a dynamic process that can be reversed via multiple mechanisms. This supports the idea that this modification does not constitute a final inactivation step that necessarily precedes protein degradation.
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PMID:Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. 1605 10

To examine the consequences of inhibiting activator protein-1 (AP-1) transcription factors in skin, transgenic mice were generated, which use the tetracycline system to conditionally express A-FOS, a dominant negative that inhibits AP-1 DNA binding. Older mice develop mild alopecia and hyperplasia of sebaceous glands, particularly around the eyes. When A-FOS was expressed during chemical-induced skin carcinogenesis, mice do not develop characteristic benign and malignant squamous lesions but instead develop benign sebaceous adenomas containing a signature mutation in the H-ras proto-oncogene. Inhibiting AP-1 activity after tumor formation caused squamous tumors to transdifferentiate into sebaceous tumors. Furthermore, reactivating AP-1 in sebaceous tumors results in a reciprocal transdifferentiation into squamous tumors. In both cases of transdifferentiation, individual cells express molecular markers for both cell types, indicating individual tumor cells have the capacity to express multiple lineages. Molecular characterization of cultured keratinocytes and tumor material indicates that AP-1 regulates the balance between the wnt/beta-catenin and hedgehog signaling pathways that determine squamous and sebaceous lineages, respectively. Chromatin immunoprecipitation analysis indicates that c-Jun binds several wnt promoters, which are misregulated by A-FOS expression, suggesting that members of the wnt pathway can be a primary targets of AP-1 transcriptional regulation. Thus, AP-1 activity regulates tumor cell lineage and is essential to maintain the squamous tumor cell identity.
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PMID:Activator protein-1 activity regulates epithelial tumor cell identity. 1688 57

Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is an adaptor protein that modulates the activation of the c-Jun NH(2) terminal kinase (JNK)/c-Jun and IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) signaling cascades in response to TNFalpha stimulation. Although many serine/threonine kinases have been implicated in TNFalpha-induced IKK activation and NF-kappaB-dependent gene expression, most of them do not directly activate IKK. Here, we report that protein kinase Czeta phosphorylates TRAF2 at Ser(55), within the RING domain of the protein, after TNFalpha stimulation. Although this phosphorylation event has a minimal effect on induction of the immediate/transient phase of IKK and JNK activation by TNFalpha, it promotes the secondary/prolonged phase of IKK activation and inhibits that of JNK. Importantly, constitutive TRAF2 phosphorylation increased both basal and inducible NF-kappaB activation and rendered Ha-Ras-V12-transformed cells resistant to stress-induced apoptosis. Moreover, TRAF2 was found to be constitutively phosphorylated in some malignant cancer cell lines and Hodgkin's lymphoma. These results reveal a new level of complexity in TNFalpha-induced IKK activation modulated by TRAF2 phosphorylation and suggest that TRAF2 phosphorylation is one of the events that are responsible for elevated basal NF-kappaB activity in certain human cancers.
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PMID:Phosphorylation of TRAF2 within its RING domain inhibits stress-induced cell death by promoting IKK and suppressing JNK activation. 1933 68

Cells avert the development of malignancy in response to deregulated oncogene expression by activating a regulated cell death pathway. However, the molecular mechanism underlying this oncogene-induced cellular death process remains unclear. Here, we show that retroviral expression of oncogenic H-ras induced cell death in a caspase-independent manner in normal cells. Inhibition of c-Jun NH2-terminal kinase (JNK) by pretreatment with SP600125 or a dominant-negative form of JNK blocked cell death. Rac1 and phosphoinositide 3-kinase (PI3K) were activated in cells overexpressing oncogenic H-ras. Inhibition of Rac1 with RacN17, a dominant-negative form of Rac1, attenuated oncogenic H-ras-induced JNK activation and subsequent cell death. Interestingly, inhibition of PI3K with LY294002 or by small interfering RNA-mediated knockdown of PI3K p85 or p110 subunits also clearly attenuated JNK activation and cell death. No cross talk was observed between Rac1 and PI3K, indicating that these pathways operate in parallel. Our findings show that JNK is necessary for oncogenic H-ras-induced, caspase-independent cell death, and that both PI3K and Rac1 activities are required for JNK activation and cell death. Determining the molecular mechanisms that mediate cell death responses to deregulated oncogenes provides a more refined understanding of cellular disposal processes in normal cells and increases our appreciation of these events as a mechanism for protecting against malignant progression.
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PMID:Oncogenic Ras signals through activation of both phosphoinositide 3-kinase and Rac1 to induce c-Jun NH2-terminal kinase-mediated, caspase-independent cell death. 1972 72


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