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)

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.
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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

Members of the c-Jun NH(2)-terminal kinase (JNK) family play crucial roles in cell activation, differentiation, and apoptosis. Although many studies have indicated that JNK1 and JNK2 have functional differences and redundancy, the upstream signaling pathway that selectively activates JNK1 or JNK2 remains unknown. In this study, we have revealed a selective mechanism of JNK activation, in which JNK2, but not JNK1, was regulated by CARMA1, a scaffold molecule, after stimulation of the T cell receptor (TCR). This CARMA1-dependent regulation of JNK2 worked through the scaffold molecule Bcl10, which was inducibly associated with JNK2 and served as a JNK-interacting protein (JIP)-like scaffold to assemble the kinases JNK2, MKK7, and TAK1. Finally, we showed that CARMA1- and Bcl10-mediated JNK2 activation had a critical role in regulating the amount of c-Jun protein. Together, our studies provide genetic evidence that JNK1 and JNK2 are differentially regulated in the TCR-signaling pathway and play different functions.
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PMID:The CARMA1-Bcl10 signaling complex selectively regulates JNK2 kinase in the T cell receptor-signaling pathway. 1718 6

Asb-4 is a gene that is specifically expressed in the hypothalamic energy homeostasis-associated areas and is down-regulated in the arcuate nucleus of fasted Sprague Dawley and obese Zucker rats. It has two functional domains, the ankyrin repeat and the SOCS box. The function of Asb-4 is unclear. We used yeast two hybridization to search for protein(s) that interact with Asb-4. With Asb-4 minus its SOCS box (Asb-4/Deltasb) as a bait, we screened mouse testis and arcuate nucleus cDNA libraries and identified G-protein pathway suppressor 1 (GPS1, also known as CSN1) as an Asb-4 interacting protein. GPS1 co-immunoprecipitated with Asb-4 both in vitro and in human HEK293 cells. When Asb-4 and GPS1 were co-transfected into HEK293 cells, expression of Asb-4 reduced the protein level of GPS1. Deletion of the SOCS box (Asb4/Deltasb) did not abolish the inhibitory effect of Asb-4 on GPS1, indicating that the SOCS box was not needed for its inhibitory effect. In NIH 3T3 L1 cells, expression of GPS1 enhanced c-Jun NH2-terminal kinase (JNK) activity. Co-expression of Asb-4 with GPS1 inhibited JNK activity. Treatment of the cells with insulin (20 nM) stimulated JNK activity. Expression of GPS1 potentiated the stimulatory effect of insulin, whereas co-expression of Asb-4 along with GPS1 inhibited JNK activity. In HEK293 cells expression of GPS1 elevated phosphorylation of insulin receptor substrate 1 (IRS-1) at serine307, co-expression of Asb-4 with GPS1 reduced the IRS-1ser307 phosphorylation. The present study demonstrates that Asb-4 interacts with GPS1 and inhibits JNK activity.
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PMID:Ankyrin repeat and SOCS box containing protein 4 (Asb-4) interacts with GPS1 (CSN1) and inhibits c-Jun NH2-terminal kinase activity. 1727 34

The sole known genetic risk factor for sporadic Alzheimer's disease (AD) is the gene encoding apolipoprotein E (APOE), but the underlying mechanism is still under debate. One hypothesis relies on an interaction between APOE and its receptors. Previous studies have shown association of LDL receptor-related protein (LRP1) with AD and we previously reported a modulation by LRP1 of the risk of AD conferred by the -499A>G promoter polymorphism of the MAPK8IP1, a gene encoding Islet-brain-1 (IB1), the human counterpart of c-Jun NH(2) terminal kinase interacting protein-1 (JIP-1). Here we tested in two independent population samples a possible impact of another receptor for APOE, namely the low-density lipoprotein receptor-related protein 8 (LRP8), on the risk of dementia. Our results did not reveal any direct impact of a LRP8 coding (Arg952Gln) mutation on the risk of AD. However, this polymorphism increased the risk of AD conferred by the MAPK8IP1 G allele.
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PMID:Low-density lipoprotein receptor-related protein 8 gene polymorphisms and dementia. 1761 63

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptotic cell death in a variety of tumor cells without significant cytotoxicity on normal cells. However, many cancer cells with apoptotic defects are resistant to treatment with TRAIL alone, limiting its potential as an anticancer therapeutic. Here, we report on the tumoricidal activity of a human single-chain fragment variable, HW1, which specifically binds to TRAIL receptor 2 (TR2) without competing with TRAIL for the binding. HW1 treatment as a single agent induces autophagic cell death in a variety of both TRAIL-sensitive and TRAIL-resistant cancer cells, but exhibits much less cytotoxicity on normal cells. The HW1-induced autophagic cell death was inhibited by an autophagy inhibitor, 3-methyladenine, or by RNA interference knockdown of Beclin-1 and Atg7. We also show that the HW1-mediated autophagic cell death occurs predominantly via the c-Jun NH(2)-terminal kinase pathway in a caspase-independent manner. Analysis of the death-inducing signaling complex induced by HW1 binding to TR2 exhibits the recruitment of TNF receptor-associated death domain and TNF receptor-associated factor 2, but not Fas-associated death domain, caspase-8, or receptor-interacting protein, which is distinct from that induced by TRAIL. Our results reveal a novel TR2-mediated signaling pathway triggering autophagic cell death and provides a new strategy for the elimination of cancer cells, including TRAIL-resistant tumors, through nonapoptotic cell death.
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PMID:A human scFv antibody against TRAIL receptor 2 induces autophagic cell death in both TRAIL-sensitive and TRAIL-resistant cancer cells. 1767 Dec 2

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis on binding to its receptors, death receptor 4 and 5 (DR4, DR5). TRAIL can also activate c-Jun N-terminal kinase (JNK) through the adaptor molecules, TNF receptor-associated factor 2 (TRAF2) and receptor-interacting protein (RIP). The role of JNK in TRAIL-induced tumour cell apoptosis is unclear. In this study, we demonstrate that JNK is activated by TRAIL in colon cancer cells. Inhibition of JNK with L-JNKI reduced rhTRAIL-induced cell death but enhanced cell death induced by selective activation of DR4 or DR5. This difference was unrelated to receptor internalisation or differential activation of c-Jun, but activation of different JNK isoforms. Our data demonstrate that JNK1, but not JNK2 is activated by rhTRAIL in the examined colon cancer cell lines. Although rhTRAIL activated both the long and short isoforms of JNK1, selective activation of DR4 or DR5 led to predominant activation of the short JNK1 isoforms (JNK1alpha1 and/or JNK1beta1). Knockdown of JNK1alpha1 by shRNA enhanced apoptosis induced by TRAIL, agonistic DR4 or DR5 antibodies. On the other hand, knockdown of the long JNK1 isoforms (JNK1alpha2 and JNK1beta2) had the opposite effect; it reduced TRAIL-induced cell death. These data indicate that the short JNK1 isoforms transmit an antiapoptotic signal, whereas the long isoforms (JNK1alpha2 or JNK1beta2) act in a proapoptotic manner.
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PMID:Differential activation of JNK1 isoforms by TRAIL receptors modulate apoptosis of colon cancer cell lines. 1935 84

A great variety of signalling pathways regulating inflammation, cell development and cell survival require NF-kappaB transcription factors, which are normally inactive due to binding to inhibitors, such as IkappaBalpha. The canonical activation pathway of NF-kappaB is initiated by phosphorylation of the inhibitor by an IkappaB kinase (IKK) complex triggering ubiquitination of IkappaB molecules by SCF-type E3-ligase complexes and rapid degradation by 26S-proteasomes. The ubiquitination machinery is regulated by the COP9 signalosome (CSN). We show that IkappaB kinases interact with the CSN-complex, as well as the SCF-ubiquitination machinery, providing an explanation for the rapid signalling-induced ubiquitination and degradation of IkappaBalpha. Furthermore, we reveal that IKK's phosphorylate not only IkappaBalpha, but also the CSN-subunit Csn5/JAB1 (c-Jun activation domain binding protein-1) and that IKK2 influences ubiquitination of Csn5/JAB1. Our observations imply that the CSN complex acts as an inhibitor of constitutive NF-kappaB activity in non-activated cells. Knock-down of Csn5/JAB1 clearly enhanced basal NF-kappaB activity and improved cell survival under stress. The inhibitory effect of Csn5/JAB1 requires a functional MPN(+) metalloprotease domain, which is responsible for cleaving ubiquitin-like Nedd8-modifications. Upon activation of cells with tumour necrosis factor-alpha, the CSN complex dissociates from IKK's allowing full and rapid activation of the NF-kappaB pathway by the concerted action of interacting protein complexes.
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PMID:Crosstalk between the NF-kappaB activating IKK-complex and the CSN signalosome. 1965 41

Increasing evidence suggests that apoptosis may be the mechanism underlying cell death in selective loss of nigral dopaminergic neurons in Parkinson's disease (PD). Previous studies strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway has a critical role in the animal model with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. In this study, we report the inhibitory effect of a peptide designated as Tat-JBD on JNKs activation. The sequence of Tat is corresponding to the cell-membrane transduction domain of human immunodeficiency virus-type 1 (HIV-1) and the sequence of an 11-amino acid peptide is corresponding to the residues of JNK-binding domain (JBD) on JNK-interacting protein-1 (JIP-1). Tat-JBD is confirmed to perturb the assembly of JIP-1-JNKs complex, inhibit the activation of JNKs induced by MPTP and consequently diminish the phosphorylation of c-Jun. It also inhibits the phosphorylation of Bcl-2 and the releasing of Bax from Bcl-2/Bax dimmers, sequentially attenuates the translocation of Bax to mitochondria, the release of cytochrome c, the activation of caspase3 and the hydrolyzation of poly-ADP-ribose-polymerase. The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by infusion of the peptide Tat-JBD in MPTP-treated mice. Our findings imply that Tat-JBD offers neuroprotection against MPTP injury via inhibiting the JNK-signaling pathway, and may provide a promising therapeutic approach for PD.
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PMID:Small peptide inhibitor of JNKs protects against MPTP-induced nigral dopaminergic injury via inhibiting the JNK-signaling pathway. 2001 Aug 51

The nuclear receptor cofactor receptor-interacting protein 140 (RIP140) is essential for cumulus cell-oocyte complex (COC) expansion, follicular rupture, and oocyte release during ovulation. The expression of many genes necessary for COC expansion is impaired in the absence of RIP140, but the studies herein document that their expression can be restored and COC expansion rescued by treatment with the epidermal growth factor (EGF)-like factor amphiregulin (AREG) both in vitro and in vivo. We demonstrate by several approaches that RIP140 is required for the expression of the EGF-like factors in granulosa cells, but the dependence of genes involved in cumulus expansion, including Ptgs2 Has2, Tnfaip6, and Ptx3, is indirect because they are induced by AREG. Treatment of granulosa cells with forskolin to mimic the effects of LH increases AREG promoter activity in a RIP140-dependent manner that 1) requires an intact cAMP response element in the proximal promoter region of the Areg gene and 2) involves its actions as a coactivator for cAMP response element-binding protein/c-Jun transcription factors. Although human chorionic gonadotropin and AREG coadministration is sufficient to restore ovulation fully in RIP140 heterozygous mice in vivo, both follicular rupture and ovulation remain impaired in the RIP140 null mice. Thus, we conclude that although the level of RIP140 expression in the ovary is a crucial factor required for the transient expression of EGF-like factors necessary for cumulus expansion, it also plays a role in other signaling pathways that induce follicular rupture.
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PMID:The nuclear receptor cofactor receptor-interacting protein 140 is a positive regulator of amphiregulin expression and cumulus cell-oocyte complex expansion in the mouse ovary. 2030 29

c-Jun N-terminal kinases (JNKs) (comprising JNK1-3 isoforms) are members of the MAPK (mitogen-activated protein kinase) family, activated in response to various stimuli including growth factors and inflammatory cytokines. Their activation is facilitated by scaffold proteins, notably JNK-interacting protein-1 (JIP1). Originally considered to be mediators of neuronal degeneration in response to stress and injury, recent studies support a role of JNKs in early stages of neurite outgrowth, including adult axonal regeneration. However, the function of individual JNK isoforms, and their potential effector molecules, remained unknown. Here, we analyzed the role of JNK signaling during axonal regeneration from adult mouse dorsal root ganglion (DRG) neurons, combining pharmacological JNK inhibition and mice deficient for each JNK isoform and for JIP1. We demonstrate that neuritogenesis is delayed by lack of JNK2 and JNK3, but not JNK1. JNK signaling is further required for sustained neurite elongation, as pharmacological JNK inhibition resulted in massive neurite retraction. This function relies on JNK1 and JNK2. Neurite regeneration of jip1(-/-) DRG neurons is affected at both initiation and extension stages. Interestingly, activated JNKs (phospho-JNKs), as well as JIP1, are also present in the cytoplasm of sprouting or regenerating axons, suggesting a local action on cytoskeleton proteins. Indeed, we have shown that JNK1 and JNK2 regulate the phosphorylation state of microtubule-associated protein MAP1B, whose role in axonal regeneration was previously characterized. Moreover, lack of MAP1B prevents neurite retraction induced by JNK inhibition. Thus, signaling by individual JNKs is differentially implicated in the reorganization of the cytoskeleton, and neurite regeneration.
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PMID:Distinct roles of c-Jun N-terminal kinase isoforms in neurite initiation and elongation during axonal regeneration. 2053 29


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