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)

p38 MAPK pathway signaling is known to participate in cell proliferation, apoptosis, and differentiation, in a manner dependent on the cellular context. The factors that determine the specific biological response in a given cell type, however, remain largely unknown. We report opposite effects of the p38 isoforms on regulation of AP-1-dependent activities by p38 activators MAPK kinase 6 (MKK6) and/or arsenite in human breast cancer cells. The p38beta isoform increases the activation of AP-1 transcriptional activities by MKK6 and/or arsenite, whereas p38gamma/p38delta inhibits or has no effect on the stimulation. The p38beta does so by increasing the levels of phosphorylated c-Jun, whereas the p38gamma and -delta isoforms may act by regulating the c-jun transcription. AP-1-dependent processes such as vitamin D receptor gene promoter activation and cellular proliferation were similarly activated by the p38beta or inhibited by the p38gamma and/or -delta isoforms. Whereas the human breast cancer cells express all four isoforms, mouse NIH 3T3 and EMT-6 cells express only some of the p38 family members, with p38beta higher in 3T3 cells but p38delta only detected in the EMT-6 line. Consistent with the positive and negative roles of p38beta and p38delta in AP-1 regulation, MKK6 stimulates AP-1-dependent transcription in NIH 3T3 but not EMT-6 cells. In support of a role of c-Jun regulation by p38 isoforms in determining AP-1 activity, the levels of endogenous c-Jun and its phosphorylated form on p38 activation are higher in NIH 3T3 cells. These results demonstrate the contrasting activities of the different p38 isoforms in transmitting the upstream signal to AP-1 and show that the expression profile of p38 isoforms determines whether the p38 signal pathway activates or inhibits AP-1-dependent processes.
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PMID:p38 isoforms have opposite effects on AP-1-dependent transcription through regulation of c-Jun. The determinant roles of the isoforms in the p38 MAPK signal specificity. 1247 89

It has been reported that overexpression of the epidermal growth factor receptor (erbB1) or its homologous receptor, HER2 (erbB2), can confer antiestrogen resistance to estrogen receptor (ER)-positive human breast cancer cells. Aberrant signaling by receptors of the erbB network up-regulates a number of signaling pathways, which include phospholipase C-gamma1, Ras-Raf-mitogen-activated protein/extracellular signal-regulated kinase kinase-mitogen-activated protein kinase, phosphatidylinositol 3'-kinase and its target, the serine/threonine kinase Akt, stress-activated protein kinases, signal transducers and activators of transcription, and c-Jun-NH(2)-terminal kinase (JNK). Akt has been reported to induce estrogen-independent transcription of ER. Here we show that transfection of ER-positive, HER2 gene-amplified BT-74 cells with an expression vector encoding dominant-negative (K179M) Akt1 partially restored the ability of tamoxifen to inhibit estradiol-stimulated ER reporter activity. Infection of MCF-7 cells with an adenovirus encoding myristoylated, constitutively active Akt induced ER reporter activity in the absence of estradiol and resulted in tamoxifen resistance of these cells in culture. Data will be presented to suggest that, in addition to mitogen-activated protein kinase, Akt is an important mediator of HER2-mediated antiestrogen resistance in human breast cancer cells.
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PMID:ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. 1253 8

Recent evidence suggests that common molecular adaptations occur during resistance to both tamoxifen and estrogen deprivation that use various signal transduction pathways, often involving cross-talk with a retained and functional estrogen receptor (ER) protein. There appear to be several different levels at which this cross-talk may occur, including peptide growth factor signaling via the type 1 tyrosine kinase growth factor receptor family [epidermal growth factor receptor (EGFR) and HER2], which may become up-regulated during endocrine treatment, ultimately being harnessed by cells to allow them hormone-independent growth. ER may remain involved in cell growth with ligand-independent phosphorylation and activation via different intracellular mitogen-activated protein kinases. ER may also become involved in non-nuclear estrogen-dependent signaling via interaction with the phosphatidylinositol 3'-kinase/Akt cell survival pathway or may interact with the stress-activated protein kinase/c-Jun-NH(2)-terminal kinase pathway. Understanding these mechanisms will permit the optimal integration of new signal transduction inhibitors (STIs) into breast cancer therapy. Preclinical approaches that have shown promise include the use of EGFR tyrosine kinase inhibitors for hormone-resistant breast cancer cells that are dependent on either EGFR or HER2 signaling. Likewise, farnesyl transferase inhibitors, mitogen-activated protein kinase inhibitors, and cell cycle inhibitors have all shown activity in experimental breast cancer models. Emerging data suggest that STIs may be more effective when given in combination with endocrine therapy either to overcome resistance or to prevent/delay emergence of the resistance phenotype. Clinical trials are in progress to determine the safety and optimal schedule for each of the various STIs, and studies of STIs in combination with aromatase inhibitors have commenced in breast cancer to see whether the therapeutic response to endocrine therapy can be enhanced further.
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PMID:Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer. 1253 10

Expression and activity of c-Jun N-terminal and p38 protein kinases were explored in malignant and non-malignant tissue samples from patients with primary breast cancer. Differential expression was observed for p38 and c-Jun N-terminal protein kinases (JNK) in samples from 14 patients in whom there were sufficient malignant and non-malignant tissue to perform the entire assays. As previously noted, Erk1,2 expression and activity were increased sharply in the malignant tissue. The p38 kinase expression and activity were increased 3-fold in breast cancer. The expression of c-Jun N-terminal protein kinase JNK1, but not JNK2, was increased 2.5-fold in malignant as compared to normal breast tissue. Immunohistochemical analysis in situ with antibodies to JNK1 revealed intense staining in samples of cancerous epithelium. In spite of a 3-fold increase in expression, malignant samples displayed a 35% decrease in the activity of this pro-apoptotic protein kinase. The expression of mitogen and extracellularly-activated protein kinase kinase (MEK)2 and MEK3, upstream protein kinases of Erkl,2 and p38, respectively, was elevated 4- to 5-fold. The upstream regulator of JNK (e.g., MEK4), however, displayed normal levels of expression, providing no basis for the reduction in JNK activity observed for breast cancer. Mitogen-activated protein kinase phosphatases (MKP)1 and MKP2 were assayed and the expression was found to be increased 5-fold and 3-fold, respectively, in malignant as compared to non-malignant samples. The reduced activity of JNK1, in spite of its overexpression, appears to reflect increased MKP activity associated with primary breast cancer. Suppression of MKP activity therapeutically may enable the expression of the pro-apoptotic signals from JNK in malignant cells.
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PMID:Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer. 1261 38

Aplidine is a promising antitumor agent derived from the Mediterranean tunicate Aplidium albicans. We have found that Aplidine at nM concentrations (10-100 nM) induced apoptosis in human leukemic cell lines and primary leukemic cell cultures from leukemic patients. Inhibition of the Fas (CD95)/Fas ligand (CD95L) signaling pathway with an antagonistic anti-Fas antibody partially inhibited Aplidine-induced apoptosis. L929 cells were resistant to Aplidine action but underwent apoptosis after transfection with human Fas cDNA. Aplidine induced a rapid and sustained c-Jun NH(2)-terminal kinase activation, and pretreatment with curcumin or SP600125 inhibited Aplidine-induced c-Jun NH(2)-terminal kinase activation and apoptosis. However, inhibition of extracellular signal-regulated kinase and p38 kinase signaling pathways did not affect Aplidine-induced apoptosis. Aplidine induced caspase-3 activation, and caspase inhibition prevented Aplidine-induced apoptosis. Aplidine failed to induce apoptosis in MCF-7 breast cancer cells, defective in caspase-3, additionally implicating caspase-3 in its proapoptotic action. Aplidine also triggered an early release of cytochrome c from mitochondria, and overexpression of bcl-2 by gene transfer abrogated mitochondrial cytochrome c release and apoptosis. Aplidine rapidly induced cleavage of Bid, a mediator that connects the Fas/CD95 cell death receptor to the mitochondrial apoptosis pathway. Primary cultures of normal human cells, including hepatocytes and resting peripheral blood lymphocytes, were spared or weakly affected after Aplidine treatment. Nevertheless, mitogen (phytohemagglutinin/interleukin-2)-activated T lymphocytes resulted sensitively to the apoptotic action of Aplidine. Thus, Aplidine is an extremely potent and rapid apoptotic inducer on leukemic cells that triggers Fas/CD95- and mitochondrial-mediated apoptotic signaling routes, and shows a rather selective apoptotic action on cancer cells and activated T cells.
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PMID:Rapid and selective apoptosis in human leukemic cells induced by Aplidine through a Fas/CD95- and mitochondrial-mediated mechanism. 1268 30

Experiments were carried out to determine the role of Raf-1 kinase in the development of drug resistance and apoptosis induced by paclitaxel. In the present study, paclitaxel sensitivity, Raf-1 activity and mitogen-activated protein kinases activation were compared in two cell lines: parental human breast cancer cells and its drug resistant variant (MCF-7/Adr) cells. Paclitaxel treatment of parental MCF-7 cells caused a marked inhibition of Raf-1 kinase activity, concomitant with its mobility shift after 18 h exposure. In addition, paclitaxel greatly increased c-Jun N-terminal protein kinase (JNK) activity whereas showing a small enhancing effect on extracellular-regulated kinases (ERK) activity. Interestingly, MCF-7/Adr cells have lower basal Raf-1 activity, yet have much higher basal ERK activity than parental cells. However, it appeared that PD 98059, which turns off ERK through mitogen-activated protein kinase kinase (MEK) inhibition, enhanced basal Raf-1 kinase activity in MCF-7/Adr cells. Thus, the findings suggest that paclitaxel-induced apoptosis is mediated by JNK and occurs in parallel with suppression of the Raf-1 kinase activity in parental MCF-7 cells. In addition, down-regulation of Raf-1 kinase, which can be induced through the sustained ERK activation, may contribute to the development of acquired resistance in MCF-7/Adr cells.
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PMID:Down-regulation of Raf-1 kinase is associated with paclitaxel resistance in human breast cancer MCF-7/Adr cells. 1269 24

Previous studies have identified RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) as a potential chemotherapeutic agent. VES induces human breast cancer cells to undergo apoptosis in a concentration- and time-dependent manner by restoring transforming growth factor beta (TGF-beta) and Fas (CD95) apoptotic signaling pathways, that contribute to the activation of c-Jun NH(2)-terminal kinase (JNK)-mediated apoptosis. The objective of these studies was to clarify biochemical events involved in VES-induced apoptosis. Data show that VES-induced apoptosis involves: (a) translocation of Bax from the cytosol to the mitochondria and cytochrome c release from the mitochondria to the cytosol as determined by Western immunoblot analyses of mitochondrial- and cytosolic-enriched cellular fractions; (b) increased permeabilization of mitochondrial membranes as determined by confocal and fluorescence-activated cell sorting analyses of loss of a mitochondrial selective fluorescent dye; (c) processing of caspase-9 and -3 but not caspase-8 to active forms and cleavage of poly(ADP-ribose) polymerase (PARP) as determined by Western immunoblot analyses using antibodies capable of detecting both proenzyme and processed enzyme forms or the intact or cleaved forms of PARP. Transient transfection of cells with antisense oligonucleotides to Bax or transient overexpression of Bcl-2 prevented VES-induced mitochondrial permeability transition and apoptosis. The use of cell-permeable caspase inhibitors indicated that caspase-9 and -3 but not caspase-8 are involved in VES-induced apoptosis. JNK inhibitor II blocked VES-induced Bax conformational change, indicating a role for JNK in Bax translocation to the mitochondria. Taken together, these data suggest that the activation of JNK, translocation of Bax to the mitochondria, increased mitochondrial membrane permeability with release of cytochrome c, and activation of caspase-9 and -3 are critical events in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.
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PMID:RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria. 1275 Feb 70

We have found previously that the retinoblastoma (Rb) suppressor associated protein 46 (RbAp46) is a gene upregulated by the Wilms' tumor suppressor, WT1, and functions as a potent growth inhibitor. To investigate the effect of RbAp46 overexpression on early development of breast cancer, we established stable cell lines from neoplastigenic breast epithelial cells, MCF10AT3B, a cell line derived from a model of human proliferative disease, to constitutively express exogenous RbAp46. We have found that expression of RbAp46 suppressed colony formation of MCF10AT3B cells in soft-agar, and inhibited tumor formation of these cells in nude mice. Expression of RbAp46 sensitized MCF10AT3B cells to apoptosis induced by serum deprivation and hydrocortisone withdrawal. Furthermore, we have found that the c-Jun NH2-terminal kinase (JNK) pathway and GADD45, a growth arrest- and DNA damage-inducible gene, are constitutively activated in RbAp46-expressing cells. Our data suggested that high levels of RbAp46 expression inhibit the tumorigenicity of neoplastigenic breast epithelial cells by facilitating JNK-dependent apoptotic cell death. Our data also suggested that dysregulation of RbAp46 gene may be involved in the early development of breast cancer.
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PMID:Overexpression of RbAp46 facilitates stress-induced apoptosis and suppresses tumorigenicity of neoplastigenic breast epithelial cells. 1276 60

Pharmacologic induction of cancer cell differentiation has potential in the treatment of breast cancer. Doxorubicin, a widely used anthracycline antibiotic, was previously reported to induce differentiation of MCF-7 breast cancer cells. We demonstrate in this study that inhibition of MCF-7 breast cancer cell growth by low dose doxorubicin (0.01 microg/ml) was accompanied by an increase in cytokeratin 8/18 and milk fat globule membrane protein expression, biomarkers for differentiation of breast cancer, as well as an increase in JNK/SAPK phosphorylation. High dose doxorubicin (10.0 microg/ml) induced apoptosis in these cells. Overexpression of dominant-inhibitory forms of JNK1 and c-Jun blocked both the differentiation and apoptotic effects of doxorubicin. These results suggest that JNK/SAPK pathway signaling plays a prominent role in doxorubicin-induced cell cycle withdrawal, differentiation and control of apoptosis in this cell system. These findings support the possibility that JNK/SAPK pathway activation may be a means of therapeutic intervention in breast cancer.
Breast Cancer Res Treat 2003 Jun
PMID:JNK/SAPK mediates doxorubicin-induced differentiation and apoptosis in MCF-7 breast cancer cells. 1284 16

Polyamine analogs have demonstrated considerable activity against many important solid tumor models including breast cancer. However, the precise mechanisms of antitumor activities of polyamine analogs are not entirely understood. The cytotoxicity of a newly developed polyamine analog compound, SL11144, against human breast cancer was assessed. Treatment of human breast cancer cell lines in culture with SL11144 decreased cell proliferation and induced programmed cell death in a time- and dose-dependent manner. SL11144 also profoundly inhibited the growth of MDA-MB-231 xenografts in host nude mice without overt toxic effects. Treatment of MDA-MB-435 cells with SL11144 led to the release of cytochrome c from mitochondria into cytosol, activation of caspase-3, and poly(ADP-ribose) polymerase cleavage. SL11144 decreased Bcl-2 and increased Bax protein levels in MDA-MB-231 cells. Furthermore, activator protein 1 transcriptional factor family member c-Jun was up-regulated by SL11144 in MDA-MB-435 and MDA-MB-231 cells, but not in MCF7 cells. In addition, significant inhibition of ornithine decarboxylase activity and a decrease in polyamine pools were demonstrated. These results demonstrate that the novel polyamine analog SL11144 has effective antineoplastic action against human breast cancer cells in vitro and in vivo and that multiple apoptotic mechanisms are associated with its cytotoxic effect in specific human breast cancer cell lines.
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PMID:A novel polyamine analog inhibits growth and induces apoptosis in human breast cancer cells. 1285 57


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