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)

Skeletal muscle undergoes a significant reduction in tension upon unloading. To explore intracellular signalling mechanisms underlying this phenomenon, we investigated twitch tension, the ratio of actin/myosin filaments, and activities of key signalling molecules in rat soleus muscle during a 3-week hindlimb suspension and 2-week reloading. Twitch tension and myofilament ratio (actin/myosin) gradually decreased during unloading but progressively recovered to initial levels during reloading. To study the involvement of stress-responsive signalling proteins during these changes, the activities of protein kinase C alpha (PKCalpha) and three mitogen-activated protein kinases (MAPKs)--c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), and p38 MAPK--were examined using immunoblotting and immune complex kinase assays. PKCalpha phosphorylation correlated positively with the tension (Pearson's r = 0.97, P < 0.001) and the myofilament ratio (r = 0.83, P < 0.01) over the entire unloading and reloading period. Treatment of the soleus muscle with a PKC activator resulted in a similar paralleled increment in both PKCalpha phosphorylation and the alpha-sarcomeric actin expression. The three MAPKs differed in the pattern of activation in that JNK activity peaked only for the first hours of reloading, whereas ERK and p38 MAPK activities remained elevated during reloading. These results suggest that PKCalpha may play a pivotal role in converting loading stress to intracellular changes in contractile proteins that determine muscle tension. Differential activation of MAPKs may also help alleviate muscle damage, modulate energy transport and/or regulate the expression of contractile proteins upon altered loading.
 ...
PMID:Differential activation of stress-responsive signalling proteins associated with altered loading in a rat skeletal muscle. 1614 53

VIP exerts a spectrum of effects as a potent anti-inflammatory factor. In addition, VIP increases expression of MUC2, a major intestinal secretory mucin. We therefore investigated the effects of VIP on the promoter activity of the 5'-flanking region of the MUC2 gene. VIP activated MUC2 transcription in human colonic epithelial cells via cAMP signaling to ERK and p38. cAMP/Epac/Rap1/B-Raf signaling was not involved in MUC2 reporter activation. Furthermore, activation of MUC2 transcription was independent of many of the reported downstream effectors of G protein-coupled receptors, such as PKC, Ras, Raf, Src, calcium, and phosphoinositide 3-kinase. VIP induced cAMP response element-binding protein (CREB)/ATF1 phosphorylation, and this was prevented by treatment with inhibitors of either MEK or p38 and by PKA and MSK1 inhibitor H89. CREB/ATF1 and c-Jun were shown to bind to an oligonucleotide encompassing a distal, conserved CREB/AP1 site in the 5'-flanking region of the MUC2 gene, and this cis element was shown to mediate promoter reporter activation by VIP. This study has identified a new, functional cis element within the MUC2 promoter and also a new pathway regulating MUC2 expression, thus providing further insight into the molecular mechanism of VIP action in the colon. These findings are relevant to the normal biology of the colonic mucosa as well as to the development of VIP as a therapeutic agent for treatment of inflammatory bowel disease.
 ...
PMID:Vasoactive intestinal peptide upregulates MUC2 intestinal mucin via CREB/ATF1. 1622 28

Protein kinase C (PKC) delta is an essential regulator of mitochondrial dependent apoptosis in epithelial cells. We have used the PKCdelta(-/-) mouse to ask if loss of PKCdelta protects salivary glands against gamma-irradiation-induced apoptosis in vivo and to explore the mechanism underlying protection from apoptosis. We show that gamma-irradiation in vivo results in a robust induction of apoptosis in the parotid glands of wild type mice, whereas apoptosis is suppressed by greater than 60% in the parotid glands of PKCdelta(-/-) mice. Primary parotid cells from PKCdelta(-/-) mice are defective in mitochondrial dependent apoptosis as indicated by suppression of etoposide-induced cytochrome c release, poly(ADP-ribose) polymerase cleavage, and caspase-3 activation. Notably, apoptotic responsiveness can be restored by re-introduction of PKCdelta by adenoviral transduction. Etoposide and gamma-irradiation-induced activation of p53 is similar in primary parotid cells and parotid glands from PKCdelta(+/+) and PKCdelta(-/-) mice, indicating that PKCdelta functions downstream of the DNA damage response. In contrast, activation of the c-Jun amino-terminal kinase is reduced in primary parotid cells from PKCdelta(-/-) cells and in parotid C5 cells, which express a dominant inhibitory mutant of PKCdelta. Similarly, c-Jun amino-terminal kinase activation is suppressed in vivo in gamma-irradiated parotid glands from PKCdelta(-/-) mice. These studies indicate an essential role for PKCdelta downstream of the p53 response and upstream of the c-Jun amino-terminal kinase activation in DNA damage-induced apoptosis in vivo and in vitro.
 ...
PMID:Suppression of apoptosis in the protein kinase Cdelta null mouse in vivo. 1645 85

A group of potential differentiation-associated genes had been identified by microarray analysis as c-Jun/AP-1 target genes essential for epithelial differentiation program. Our previous study showed that c-Jun/AP-1 could bind and activate these gene promoters in vivo using chromatin immunoprecipitation. To further understand how the mitogen-activated protein kinase signaling pathways regulate AP-1 activity and expression of c-Jun target genes, our strategy was based on the use of 12-o-tetradecanoylophorbol-13-acetate (TPA) and pharmacological reagents to induce or block c-Jun expression. The mRNA and protein expression of these genes increased in response to TPA-induced c-Jun/AP-1 expression. Inhibitors of JNK (SP600125) and PKC (GF109203X) mainly blocked expression and phosphorylation of c-Jun, while inhibition of MEK-ERK activity with PD98059 (an inhibitor of MEK) had little effect. Expression of involucrin and keratin 4 in response to TPA was attenuated by pretreatments with GF109203X and SP600125, but not PD98059, suggesting involvement of PKC and JNK in this response. Taken together, these results suggested that differentiation-associated genes were regulated by TPA-induced c-Jun/AP-1 mainly via a PKC/JNK pathway in esophageal cancer cell line KYSE450.
 ...
PMID:Differentiation-associated genes regulated by TPA-induced c-Jun expression via a PKC/JNK pathway in KYSE450 cells. 1648 Sep 52

We have recently identified apelin as a novel adipokine up-regulated by insulin and obesity. Since obesity and insulin resistance are associated with chronically elevated levels of both insulin and TNFalpha, the present study was performed to investigate a putative regulation of apelin expression in adipocytes by TNFalpha. Herein, we report a tight correlation between apelin and TNFalpha expression in adipose tissue of lean and obese humans. Apelin regulation by TNFalpha was further studied in cultured explants of human adipose tissue. The endogenous expression of TNFalpha in adipocytes isolated from the explants was accompanied by a 6-9 h subsequent increase of apelin expression in adipocytes. This increase was reversed by inhibiting TNFalpha expression with 100 microM isobutylmethylxanthine. In different mouse models of obesity, expression of both TNFalpha and apelin was also significantly increased in adipocytes of obese mice. Furthermore, short-term exposure to an i.p. injection of TNFalpha in C57Bl6/J mice induced an increase of apelin expression in adipose tissue as well as apelin plasma levels. Finally, a direct positive effect of TNFalpha has been shown in differentiated 3T3F442A adipocytes on apelin expression and secretion. The signaling pathways of TNFalpha for the induction of apelin were dependent of PI3-kinase, c-Jun NH2-terminal kinase (JNK), and MAPK but not PKC activation. All together, these findings suggest that apelin might be a candidate to better understand potential links between obesity and associated disorders such as inflammation and insulin resistance.
 ...
PMID:TNFalpha up-regulates apelin expression in human and mouse adipose tissue. 1672 81

Oxytocin (OT) is a potent uterine agonist. Its receptor (OTR) is a G protein-coupled receptor that is downregulated by prolonged exposure to OT. We hypothesized that activation of PKC mediated this OT-induced decrease in OTR expression. Diminished PKC activity in late pregnancy could underlie the increased expression of uterine OTR preceding labor onset. Using cell cultures of transformed human uterine myocytes, we determined the effects of PKC agonists and antagonists on the expression of OTR. We also explored the effects of overexpression of activator protein-1 (AP-1, a mediator of many PKC- and phorbol ester-induced effects) using adenoviral expression vectors for the AP-1 subunits c-Jun and c-Fos. Stimulation of PKC using the phorbol ester 12-O-tetradecanoylphorbol 13-acetate caused a rapid, significant (P < or = 0.05) increase in c-Jun and c-Fos concentrations but a significant decrease in mRNA for OTR within 6 h followed by a significant decrease in OT binding by 24 h. Adenoviral infection of the cells with expression vectors for c-Jun and c-Fos increased the AP-1 subunits but had no effect on OTR expression. Furthermore, there were no changes in c-Fos or c-Jun levels in human intrauterine tissues around the time of labor onset, as measured by Western analyses. We conclude that phorbol ester treatment decreases OTR expression, likely through a mechanism that does not involve AP-1.
 ...
PMID:Phorbol ester treatment of human myometrial cells suppresses expression of oxytocin receptor through a mechanism that does not involve activator protein-1. 1675 45

Protein kinase C (PKC) triggers cellular signals that regulate proliferation or death in a cell- and stimulus-specific manner. Although previous studies have demonstrated that activation of PKC with phorbol 12-myristate 13-acetate (PMA) protects cells from apoptosis induced by a number of mechanisms, including death receptor ligation, little is known about the effect or mechanism of PMA in the necrotic cell death. Here, we demonstrate that PMA-mediated activation of PKC protects against tumor necrosis factor (TNF)-induced necrosis by disrupting formation of the TNF receptor (TNFR)1 signaling complex. Pretreatment with PMA protected L929 cells from TNF-induced necrotic cell death in a PKC-dependent manner, but it did not protect against DNA-damaging agents, including doxorubicin (Adriamycin) and camptothecin. Analysis of the upstream signaling events affected by PMA revealed that it markedly inhibited the TNF-induced recruitment of TNFR1-associated death domain protein (TRADD) and receptor-interacting protein (RIP) to TNFR1, subsequently inhibiting TNF-induced activation of nuclear factor-kappaB and c-Jun NH2-terminal kinase (JNK). However, JNK inhibitors do not significantly affect TNF-induced necrosis, suggesting that the inhibition of JNK activation by PMA is not part of the antinecrotic mechanism. In addition, PMA acted as an antagonist of TNF-induced reactive oxygen species (ROS) production, thereby suppressing activation of ROS-mediated poly(ADP-ribose)polymerase (PARP), and thus inhibiting necrotic cell death. Furthermore, during TNF-induced necrosis, PARP was significantly activated in wild-type mouse embryonic fibroblast (MEF) cells but not in RIP-/- or TNFR-associated factor 2-/-MEF cells. Taken together, these results suggest that PKC activation ensures effective shutdown of the death receptor-mediated necrotic cell death pathway by modulating formation of the death receptor signaling complex.
 ...
PMID:Phorbol 12-myristate 13-acetate protects against tumor necrosis factor (TNF)-induced necrotic cell death by modulating the recruitment of TNF receptor 1-associated death domain and receptor-interacting protein into the TNF receptor 1 signaling complex: Implication for the regulatory role of protein kinase C. 1679 36

Epidermal growth factor receptor (EGFR) is a critical mediator of several types of epithelial cancers. Skin cancer arising from exposure to ultraviolet B irradiation (UVB) from the sun is a prominent form of human cancer. Recent data indicate that in addition to cognate ligands, EGFR is activated by UVB irradiation. We used pharmacological and genetic approaches to investigate the function of EGFR in mediating UVB-induced signal transduction in human skin keratinocyte HaCaT cells. Pharmacological inhibition of EGFR tyrosine kinase significantly inhibited UVB-mediated induction of ERK, p38, and JNK MAP kinases, and their effectors, transcription factors c-Fos and c-Jun. Inhibition of UVB activation of EGFR also suppressed activation of AKT-, PKC-, and PKA-dependent signal transduction pathways. B82 mouse L cells devoid of EGFR were used to further investigate EGFR dependence of UVB-induced signal transduction. UVB failed to induce ERK, and JNK activation was reduced 60% in B82 cells compared to B82K+ cells, which express EGFR. In addition, UVB induced both c-Fos and c-Jun proteins in B82K+ cells, whereas neither were induced in B82 cells. Taken together, these data demonstrate that EGFR is required for UVB-mediated induction of multiple signaling pathways that are known to mediate tumor formation in skin.
 ...
PMID:Epidermal growth factor receptor is a critical mediator of ultraviolet B irradiation-induced signal transduction in immortalized human keratinocyte HaCaT cells. 1693 59

Mechanosensory hair cells are susceptible to apoptotic death in response to exposure to ototoxic drugs, including aminoglycoside antibiotics. The c-Jun n-terminal kinase (JNK) is a stress-activated protein kinase that can promote apoptotic cell death in a variety of systems. Inhibition of the JNK signaling pathway can prevent aminoglycoside-induced death of cochlear and vestibular sensory hair cells. We used an in vitro preparation of utricles from adult mice to examine the role of JNK activation in aminoglycoside-induced hair cell death. CEP-11004 was used as an indirect inhibitor of JNK signaling. Immunohistochemistry showed that both JNK and its downstream target c-Jun are phosphorylated in hair cells of utricles exposed to neomycin. CEP-11004 inhibited neomycin-induced phosphorylation of both JNK and c-Jun. CEP-11004 inhibited hair cell death in utricles exposed to moderate doses of neomycin. However, the results were not uniform across the dose-response function; CEP-11004 did not inhibit hair cell death in utricles exposed to high-dose neomycin. The CEP-11004-induced protective effect was not due to inhibition of PKC or p38, since neither Chelerythrine nor SB203580 could mimic the protective effect of CEP-11004. In addition, inhibition of JNK inhibited the activation of caspase-9 in hair cells. These results indicate that JNK plays an important role in neomycin-induced vestibular hair cell death and caspase-9 activation.
 ...
PMID:JNK signaling in neomycin-induced vestibular hair cell death. 1700 44

Hypertension is known to exacerbate diabetic complications, such as retinopathy and nephropathy. Apoptosis of retinal vascular pericytes has been well established as the earliest conceivable change in diabetic retinopathy. In this study, we investigated the contribution of cyclic stretch, which mimics a hypertensive state to pericyte apoptosis. A 48-hour cyclic stretch induced DNA fragmentation in porcine retinal pericytes and increased the number of TUNEL+ cells at a pathophysiologically relevant extension level (10%/60 cycles per minute). Stretch also increased intracellular reactive oxygen species generation and increased c-Jun NH(2)-terminal kinase phosphorylation in a time- and magnitude-dependent manner, which were reduced by the nicotinamide-adenine dinucleotide phosphate oxidase inhibitor diphenylene iodonium or dominant-negative protein kinase C-delta. Stretch activated protein kinase C-delta and increased its association with p47phox. Stretch induced cleavage of caspase-9 and -3 and increased caspase-3 activity. Protein kinase C-delta or c-Jun NH(2)-terminal kinase inhibition normalized stretch-induced caspase-3 activity and prevented stretch-induced apoptosis. These data indicate that cyclic stretch induces apoptosis in porcine retinal pericytes by activation of the reactive oxygen species-c-Jun NH(2)-terminal kinase-caspase cascades, suggesting a novel molecular mechanism to explain the exacerbation of early diabetic retinopathy by concomitant hypertension.
 ...
PMID:Cyclic stretch-induced reactive oxygen species generation enhances apoptosis in retinal pericytes through c-jun NH2-terminal kinase activation. 1715 82


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