Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When MCF-7 cells were incubated with 10 or 20 microM CdCl(2), p53 protein level increased after 18 h. Among serines in p53 protein immunoprecipitated from cells treated with CdCl(2), only Ser 15 was phosphorylated. No clear phosphorylation was found on Ser 6, 9, 20, 37, and 392. Accumulation of p53 protein phosphorylated at Ser 15 was also found after 18 h exposure. While phosphorylation of extracellular signal-regulated protein kinase, c-Jun NH2-terminal kinase and p38 was found in cells treated with CdCl(2), treatment with U0126, LL-Z1640-2, or SB203580 did not suppress Ser 15 phosphorylation. On the other hand, treatment with wortmannin or caffeine suppressed CdCl(2)-induced Ser 15 phosphorylation and accumulation of p53 protein. The present results showed that cadmium induces phosphorylation of p53 at Ser 15 in MCF-7 cells depending on phosphatidylinositol 3-kinase related kinases, but not on mitogen-activated protein kinases.
 ...
PMID:Cadmium induces phosphorylation of p53 at serine 15 in MCF-7 cells. 1130 31

Cyclin D1 gene expression is induced by 17beta-estradiol (E2) in human breast cancer cells and is important for progression of cells through the G(1) phase of the cell cycle. The mechanism of activation of cyclin D1 is mitogen- and cell context-dependent, and this study describes the role of multiple promoter elements required for induction of cyclin D1 by E2 in estrogen receptor (ER)-positive ZR-75 breast cancer cells. Transcriptional activation of cyclin D1 by E2 was dependent, in part, on a proximal cAMP-response element at -66, and this was linked to induction of protein kinase A-dependent pathways. These results contrasted to a recent report showing that induction of cyclin D1 by E2 in ER-positive MCF-7 and HeLa cells was due to up-regulation of c-jun and subsequent interaction of c-Jun-ATF-2 with the CRE. Moreover, further examination of the proximal region of the cyclin D1 promoter showed that three GC-rich Sp1-binding sites at -143 to -110 were also E2-responsive, and interaction of ERalpha and Sp1 proteins at these sites was confirmed by electromobility shift and chromatin immunoprecipitation assays. Thus, induction of cyclin D1 by E2 in ZR-75 cells is regulated through nuclear ERalpha/Sp1 and epigenetic protein kinase A activation pathways, and our results suggest that this mechanism may be cell context-dependent even among ER-positive breast cancer cell lines.
 ...
PMID:Estrogen regulation of cyclin D1 gene expression in ZR-75 breast cancer cells involves multiple enhancer elements. 1141 May 92

Estrogens are direct mitogens for hormone-responsive human breast cancercells, where they promote cell cycle progression and induce transcriptional activation of "immediate early" and cyclin genes. Nongenomic signaling by estrogens, including rapid changes of mitogen-activated protein(MAP) kinase and other signal-transduction-cascades activity, has been proposed to be essential for the mitogenic actions of these hormones and their nuclear receptors. Because regulation of gene transcription is considered a key step in cell cycle control by mitogenic protein kinase cascades, here we investigated the possibility that estrogen might induce the activation of extracellular signal-regulated kinase (Erk) 1/2-, c-Jun NH(2)-terminal kinase-, p38- or protein kinase A-responsive transcription factors in the cell nucleus during stimulation of early G(1) progression, a timing coincident with the maximum effects of these hormones on such enzyme activity. No significant changes in protein kinase-mediated transcription factor activity could be detected here after estrogen stimulation of either MCF-7 or ZR-75.1 cells. Furthermore, these steroids were able to induce activation of the human CCND1 gene promoter, accumulation of cyclin D1 and pRb phosphorylation, all key events in cell cycle stimulation by mitogens, even in the presence of Erk1/2 activation blockade by a MAP kinase-activating kinase (Mek)1/2 inhibitor. Thus, estrogens do not appear to convey significant protein kinase-dependent signaling to the cell nucleus during the early phases of human breast cancer cell stimulation. Furthermore, hormonal regulation of G(1) gene transcription can occur even without additional activation of the Mek-Erk1/2 pathway by estrogen receptors.
 ...
PMID:Estrogens do not modify MAP kinase-dependent nuclear signaling during stimulation of early G(1) progression in human breast cancer cells. 1152 26

The signaling connection between mitogen-activated protein kinases(MAPKs) and nuclear steroid receptors is complex and remains mostly unexplored. Here we report that stress-activated protein kinases p38 and JNK trans-activate nuclear steroid vitamin D receptor (VDR) gene and increase vitamin D(3)-dependent growth inhibition in human breast cancer cells. Activation of p38 and JNK by an active MAPK kinase 6 stimulates VDR promoter activity independently of the ligand vitamin D(3) and estrogen receptor expression. Moreover, stimulation of the endogenous stress pathways by adenovirus-mediated delivery of recombinant MAPK kinase 6 also activates VDR and sensitizes MCF-7 cells to vitamin D(3)-dependent growth inhibition. Both the p38 and JNK MAPK pathways and the downstream transcription factor c-Jun/AP-1 are required for the VDR stimulation, as revealed by application of their dominant negatives, the specific p38 inhibitor SB203580, and site-directed mutagenesis of the AP-1 element in the VDR promoter. The essential role of the p38 and JNK stress pathways in up-regulation of VDR expression is further confirmed by using the chemical stimulator arsenite. These results establish a signaling connection between the stress MAPK pathways and steroid hormone receptor VDR expression and thereby offer new insights into regulation of cell growth by the MAPK pathways through regulation of vitamin D(3)/VDR activity.
 ...
PMID:The p38 and JNK pathways cooperate to trans-activate vitamin D receptor via c-Jun/AP-1 and sensitize human breast cancer cells to vitamin D(3)-induced growth inhibition. 1198 7

Curcumin, the major component of the spice turmeric, is used as a coloring and flavoring additive in many foods and has attracted interest because of its anti-inflammatory and chemopreventive activities. However, this agent also inhibits the generation of reactive oxygen species (ROS) and the c-Jun NH(2)-terminal kinase (JNK) pathway, and because many chemotherapeutic drugs generate ROS and activate JNK in the course of inducing apoptosis, we considered the possibility that curcumin might antagonize their antitumor efficacy. Studies in tissue culture revealed that curcumin inhibited camptothecin-, mechlorethamine-, and doxorubicin-induced apoptosis of MCF-7, MDA-MB-231, and BT-474 human breast cancer cells by up to 70%. Inhibition of programmed cell death was time and concentration dependent, but occurred after relatively brief 3-h exposures, or at curcumin concentrations of 1 microM that have been documented in Phase I chemoprevention trials. Under these conditions, curcumin exhibited antioxidant properties and inhibited both JNK activation and mitochondrial release of cytochrome c in a concentration-dependent manner. Using an in vivo model of human breast cancer, dietary supplementation with curcumin was found to significantly inhibit cyclophosphamide-induced tumor regression. Such dietary supplementation was accompanied by a decrease in the activation of apoptosis by cyclophosphamide, as well as decreased JNK activation. These findings support the hypothesis that dietary curcumin can inhibit chemotherapy-induced apoptosis through inhibition of ROS generation and blockade of JNK function, and suggest that additional studies are needed to determine whether breast cancer patients undergoing chemotherapy should avoid curcumin supplementation, and possibly even limit their exposure to curcumin-containing foods.
 ...
PMID:Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. 1294 49

We have found that ecteinascidin-743 (ET-743) inhibited cell proliferation at 1-10 ng/ml, leading to S and G(2)/M arrest and subsequent apoptosis, and induced early apoptosis without previous cell cycle arrest at 10-100 ng/ml in cancer cells. ET-743-mediated apoptosis, did not involve Fas/CD95. ET-743 induced c-Jun NH(2)-terminal kinase (JNK) and caspase-3 activation, and JNK and caspase inhibition prevented ET-743-induced apoptosis. ET-743 failed to promote apoptosis in caspase-3-deficient MCF-7 cells, further implicating caspase-3 in its proapoptotic action. Overexpression of bcl-2 by gene transfer abrogated ET-743-induced apoptosis, but cells underwent cell cycle arrest. ET-743 triggered cytochrome c release from mitochondria that was inhibited by Bcl-2 overexpression. Inhibition of transcription or protein synthesis did not prevent ET-743-induced apoptosis, but abrogated ET-743-induced cell cycle arrest. Microarray analyses revealed changes in the expression of a small number of cell cycle-related genes (p21, GADD45A, cyclin G2, MCM5, and histones) that suggested their putative involvement in ET-743-induced cell cycle arrest. These data indicate that ET-743 is a very potent anticancer drug showing dose-dependent cytostatic and proapoptotic effects through activation of two different signaling pathways, namely a transcription-dependent pathway leading to cell cycle arrest and a transcription-independent route leading to rapid apoptosis that involves mitochondria, JNK, and caspase-3.
 ...
PMID:Differential cytostatic and apoptotic effects of ecteinascidin-743 in cancer cells. Transcription-dependent cell cycle arrest and transcription-independent JNK and mitochondrial mediated apoptosis. 1219 19

Microtubule-interfering agents are widely used in cancer chemotherapy, and prognostic results vary significantly from tumor to tumor, depending on the p53 status. In preliminary experiments, we compared the expression and phosphorylation profiles of more than 100 protein kinases and protein phosphatases in human colorectal carcinoma cell line HCT116 between p53+/+ and p53-/- cells in response to short term nocodazole treatment through application of Kinetworks immunoblotting screens. Among the proteins tracked, the regulation of the phosphorylation of c-Jun N-terminal kinase (JNK)1/2 at Thr-183/Tyr-185 was the major difference between p53+/+ and p53-/- cells. With the loss of the p53 gene, the levels of phosphorylation of Ser-63 of c-Jun and Thr-183/Tyr-185 of JNK1/2 in p53-/- cells did not increase as markedly as in p53+/+ cells in response to a 1-h treatment with nocodazole or other microtubule-disrupting drugs such as vinblastine and colchicine. Similar observations were also made in MCF-7 and A549 tumor cells, which were rendered p53-deficient by E6 oncoprotein expression. However, arsenate-induced JNK activation in p53-/- cells was preserved. Inhibition of p53 expression by its antisense oligonucleotide also attenuated nocodazole-induced JNK activation in p53+/+ cells. Surprisingly, cotransfection of p53+/+ cells with dominant negative mutants of JNK isoforms and treatment of p53+/+ cells with the JNK inhibitor SP600125 actually further enhanced apoptosis in p53+/+ cells by up to 2-fold in response to nocodazole. These findings indicate that inhibition of p53-mediated JNK1/2 activity in certain tumor cells could serve to enhance the apoptosis-inducing actions of cancer chemotherapeutic agents that disrupt mitotic spindle function.
 ...
PMID:Nocodazole-induced p53-dependent c-Jun N-terminal kinase activation reduces apoptosis in human colon carcinoma HCT116 cells. 1222 Oct 76

The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) regulates immune responses, inflammation, and programmed cell death (apoptosis). TNF-alpha exerts its biological activities by activating multiple signaling pathways, including IkappaB kinase (IKK), c-Jun N-terminal protein kinase (JNK), and caspases. IKK activation inhibits apoptosis through the transcription factor NF-kappaB, whose target genes include those that encode inhibitors of both caspases and JNK. Despite activation of the antiapoptotic IKK/NF-kappaB pathway, TNF-alpha is able to induce apoptosis in cells sensitive to it, such as human breast carcinoma MCF-7 and mouse fibroblast LM cells. The molecular mechanism underlying TNF-alpha-induced apoptosis is incompletely understood. Here we report that in TNF-alpha-sensitive cells activation of the IKK/NF-kappaB pathway fails to block TNF-alpha-induced apoptosis, although its inactivation still promotes TNF-alpha-induced apoptosis. Interestingly, TNF-alpha-induced apoptosis is suppressed by inhibition of the JNK pathway but promoted by its activation. Furthermore, activation of JNK by TNF-alpha was transient in TNF-alpha-insensitive cells but prolonged in sensitive cells. Conversion of JNK activation from prolonged to transient suppressed TNF-alpha-induced apoptosis. Thus, absence of NF-kappaB-mediated inhibition of JNK activation contributes to TNF-alpha-induced apoptosis.
 ...
PMID:The absence of NF-kappaB-mediated inhibition of c-Jun N-terminal kinase activation contributes to tumor necrosis factor alpha-induced apoptosis. 1244 76

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.
 ...
PMID:ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. 1253 8

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.
 ...
PMID:Rapid and selective apoptosis in human leukemic cells induced by Aplidine through a Fas/CD95- and mitochondrial-mediated mechanism. 1268 30


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>