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)

The nuclear receptor mouse retinoid X receptor alpha (mRXRalpha) was shown to be constitutively phosphorylated in its NH2-terminal A/B region, which contains potential phosphorylation sites for proline-directed Ser/Thr kinases. Mutants for each putative site were generated and overexpressed in transfected COS-1 cells. Constitutively phosphorylated residues identified by tryptic phosphopeptide mapping included serine 22 located in the A1 region that is specific to the RXRalpha1 isoform. Overexpression and UV activation of the stress-activated kinases, c-Jun NH2-terminal kinases 1 and 2 (JNK1 and JNK2), hyperphosphorylated RXRalpha, resulting in a marked decrease in its electrophoretic mobility. This inducible hyperphosphorylation involved three residues (serines 61 and 75 and threonine 87) in the B region of RXRalpha and one residue (serine 265) in the ligand binding domain (E region). Binding assays performed in vitro with purified recombinant proteins demonstrated that JNKs did not interact with RXRalpha but bound to its heterodimeric partners, retinoic acid receptors alpha and gamma (RARalpha and RARgamma). Hyperphosphorylation by JNKs did not affect the transactivation properties of either RXRalpha homodimers or RXRalpha/RARalpha heterodimers in transfected cultured cells.
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PMID:Hyperphosphorylation of the retinoid X receptor alpha by activated c-Jun NH2-terminal kinases. 1038 91

Vasoactive intestinal peptide (VIP) gene expression is highly restricted throughout the neuroaxis and regulated by extracellular factors that activate tyrosine- or serine/threonine-directed protein kinase pathways. Cytokine, cyclic AMP, and tissue-specific response elements on the VIP gene have been characterized. Those mediating responsiveness to protein kinase C have not. The endogenous VIP gene and a 5.2-kilobase pair (kb) VIP-luciferase reporter gene, are up-regulated by phorbol 12-myristate 13-acetate (PMA) in SK-N-SH neuroblastoma cells. PMA stimulation was abolished by deletion of sequences at -1.37 to -1.28 or -1.28 to -0.904 kb, but not by removal of the single phorbol ester response element (TRE; TGACTCA) located at -2.25 kb. Mutation of sites at -1.32 or -1.20 that mediate neurotrophin responsiveness of the VIP gene (Symes, A., Lewis, S., Corpus, L., Rajan, P., Hyman, S. E., and Fink, J. S. (1994) Mol. Endocrinol. 8, 1750-1763) each reduced PMA induction in SK-N-SH cells by >50%, and double mutation abolished it. The two mutations also reduced basal VIP reporter gene transcription in SH-EP neuroblastoma cells expressing VIP constitutively. Both cis-active elements bound pre-existing AP-1 proteins in SH-EP- or PMA-stimulated SK-N-SH cell nuclear extracts. The AP-1 complex at both sites contained a Fos-related protein with c-Jun in SH-EP cells and c-Fos with a Jun-related protein in SK-N-SH cells. Recruitment of combinatorially distinct AP-1 complexes to these elements may underlie cell type-specific regulation of the VIP gene.
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PMID:Two separate cis-active elements of the vasoactive intestinal peptide gene mediate constitutive and inducible transcription by binding different sets of AP-1 proteins. 1046 93

The role of IL-6 in collagen production and tissue remodeling is controversial. In Rat-1 fibroblasts, we measured the effect of IL-6 on matrix metalloproteinase-13 (MMP-13), c-jun, junB, and c-fos gene expression, binding of activator protein 1 (AP1) to DNA, amount of AP1 proteins, immunoreactive MMP-13 and TIMP-1 proteins, and Jun N-terminal kinase activity. We show that IL-6 increased MMP-13-mRNA and MMP-13 protein. These effects were exerted by acting on the AP1-binding site of the MMP-13 promoter, as shown by transfecting cells with reporter plasmids containing mutations in this element. Mobility shift assays demonstrated that IL-6 induced the DNA binding activity of AP1. This effect was accompanied by a marked increase in c-Jun, JunB, and c-Fos mRNA, as well as in c-Jun protein and its phosphorylated form. The latter is not due to increased Jun N-terminal kinase activity but to a decreased serine/threonine phosphatase activity. We conclude that IL-6 increases interstitial MMP-13 gene expression at the promoter level. This effect seems to be mediated by the induction of c-jun, junB, and c-fos gene expression, by the binding of AP1 to DNA, by increasing phosphorylated c-Jun, and by the inhibition of serine/threonine phosphatase activity. These effects of IL-6 might contribute to remodeling connective tissue.
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PMID:Interleukin-6 increases rat metalloproteinase-13 gene expression through stimulation of activator protein 1 transcription factor in cultured fibroblasts. 1052 86

Jun transcription factors have been implicated in the regulation of cell proliferation, differentiation and apoptosis. We have investigated the relationship between Jun expression and cell death in the developing chicken inner ear. c-jun and junD transcripts were expressed in the epithelium of the otic placode and otic vesicle. c-jun expression was restricted to the dorsal area of the otic pit (stages 14-17), dorsal otic vesicle and cochleo-vestibular ganglion (stages 18-20). junD expression was transient and occurred in the dorsal and upper medial aspects of the otic pit and otic cup, but it was down-regulated in the otic vesicle. A parallel TUNEL analysis revealed that expression of c-jun co-located within areas of intense apoptosis. Furthermore, phosphorylation of c-Jun at serine-63 by Jun amino-terminal-kinases was detected in the dorsal otic pit, otic vesicle and cochleo-vestibular ganglion. c-Jun protein exhibited DNA binding activity, as assessed by gel mobility shift assays. The association between c-Jun and apoptosis was further demonstrated by studying nerve growth factor-induced apoptosis in cultured otic vesicles. Nerve growth factor-induced cell death and c-Jun phosphorylation that were suppressed by insulin-like growth factor-I and by viral-mediated overexpression of Raf, which had survival effects. In conclusion, the precise regulation of the expression and activity of Jun proteins in the otic primordium suggests that it may operate as a fundamental mechanism during organogenesis.
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PMID:Pattern of expression of the jun family of transcription factors during the early development of the inner ear: implications in apoptosis. 1054 57

Transforming growth factor-beta (TGFbeta) enhances transcription from reporter genes regulated by a single consensus cAMP-response element (CRE) upon transfection into the immortalized human keratinocyte cell line, HaCaT. Whereas both CRE-binding protein (CREB) and c-Jun present in extracts of unstimulated cells can complex with a CRE in gel-shift experiments, TGFbeta treatment increases the amount of c-Jun found in the complex. Overexpression of c-Jun is sufficient to increase CRE and GAL4-CREB-dependent transcription and mimics the stimulatory effects of TGFbeta on transcription from either reporter gene. Surprisingly, although a portion of CREB in unstimulated cells is phosphorylated on the activating serine residue, Ser-133, this level of phospho-CREB is not altered by TGFbeta treatment. In fact, the CREB-dependent transcriptional effects of TGFbeta or c-Jun do not require phosphorylation of Ser-133, although CREB-binding protein (CBP) is required as evidenced by the observation that the adenoviral oncoprotein E1A can block the effects of both agents. c-Jun enhancement of CRE or GAL4-CREB-dependent transcription neither requires the DNA-binding nor N-terminal domains of c-Jun. Collectively, these results are consistent with a model in which signaling pathways initiated by TGFbeta can stimulate CREB-dependent transcription by increasing the cellular concentration of c-Jun, which participates in activation of the CBP-containing transcription complex.
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PMID:c-Jun enhancement of cyclic adenosine 3',5'-monophosphate response element-dependent transcription induced by transforming growth factor-beta is independent of c-Jun binding to DNA. 1059 80

The proline-, glutamic acid-, serine- and threonine-enriched protein tyrosine phosphatase PEP, which is expressed primarily in hematopoietic cells, was recently discovered to be physically associated with the 50-kDa cytosolic protein tyrosine kinase (PTK) Csk, an important suppressor of Src family PTK, including Lck and Fyn in T cells. We report that this phosphatase has an inhibitory effect on TCR-induced transcriptional activation of the c-fos proto-oncogene and elements from the IL-2 gene promoter. Catalytically inactive mutants of PEP had no effects in these assays. Expression of PEP also reduced activation of the N-terminal c-Jun kinase Jnk2 in response to receptor ligation, but not in response to UV light. In agreement with a more receptor-proximal site of action, we found that PEP reduced the TCR-induced increase in tyrosine phosphorylation of an Lck mutant, Lck-Y505F, which is only phosphorylated on tyrosine 394, the positive regulatory site. Finally, we observed that PEP reduced c-fos activation in a synergistic manner with Csk, supporting the notion that these two enzymes form a functional team acting on Src family kinases involved in TCR signaling.
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PMID:Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. 1060 92

LPS elicits several immediate proinflammatoy responses in peripheral blood leukocytes via a recently described pathway including CD14, Toll-like receptors (TLR), serine-threonine kinases, and NF-kappaB transcription factor. However, the functional responses of intestinal epithelial cells (IEC) to stimulation with LPS are unknown. Expression of mRNA and protein for CD14 and TLRs were assessed by RT-PCR, immunoblotting, and immunohistochemistry in mouse and human IEC lines. LPS-induced activation of signaling pathways (p42/p44 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase (JNK), p38, p65, NF-kappaB) were assessed by immunoblotting and gel shifts. CD14 mRNA and protein expression were not detectable in IEC. However, human TLR2, TLR3, and TLR4 mRNA were present in IEC. TLR4 protein was expressed in all cell lines; however, TLR2 protein was absent in HT29 cells. Immunofluorescent staining of T84 cells demonstrated the cell-surface presence of the TLRs. LPS-stimulation of IEC resulted in activation (>1.5-fold) of the three members of the MAPK family. In contrast, LPS did not significantly induce activation of JNK and p38 in CMT93 cells, p38 in T84 cells and MAPK and JNK in HT29 cells. Downstream, LPS activated NF-kappaB in IEC in a time-, dose-, and serum-dependent manner. IEC express TLRs that appear to mediate LPS stimulation of specific intracellular signal transduction pathways in IEC. Thus, IEC may play a frontline role in monitoring lumenal bacteria.
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PMID:Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors. 1062 46

In tobacco cells, osmotic stress induced the rapid activation of two protein kinases that phosphorylate myelin basic protein. Immunological studies demonstrated that the 48-kD kinase is the salicylic acid-induced protein kinase (SIPK), a member of the mitogen-activated protein kinase family. SIPK was activated 5 to 10 min after the cells were exposed to osmotic stresses, and its activity persisted for approximately 30 min. In contrast, the 42-kD kinase was activated within 1 min after osmotic stress, and its activity was maintained for approximately 2 hr. Moreover, in addition to myelin basic protein, the 42-kD kinase phosphorylated casein and two transcription factors, c-Jun and ATF-2. This latter enzyme was inactivated by a serine/threonine-specific phosphatase but, unlike SIPK, was not affected by a tyrosine-specific phosphatase. After the 42-kD kinase was purified to apparent homogeneity, tryptic peptide analysis indicated that it is a homolog of Arabidopsis serine/threonine kinase1 (ASK1).
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PMID:Osmotic stress induces rapid activation of a salicylic acid-induced protein kinase and a homolog of protein kinase ASK1 in tobacco cells. 1063 15

Protein serine/threonine (ser/thr) phosphorylation is an early signaling event in macrophage activation. We investigated the changes in stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) activity and effects of phosphatase inhibition on alveolar macrophage (AM) function in rats challenged with intratracheal endotoxin. Animals were sacrificed 90 min post intratracheal lipopolysaccharide (LPS, 100 microg/rat) challenge. AMs were incubated with or without phosphatase inhibitors at 37 degrees C for 30 min. Phagocytosis, CD18 expression, SAPK/JNK and phosphatase activities of AMs were determined. LPS challenge activated SAPK/JNK activity and enhanced phagocytosis of AMs without altering phosphatase activity in these cells. Inhibition of phosphatase 1 and 2A activity with okadaic acid and calyculin A exerted a bi-phasic effect on AM phagocytic function. Okadaic acid at a concentration of 1 microM increased the mean channel fluorescence intensity (MCF) and the percentage of cells engaged in phagocytosis (percent phagocytosis) in AMs from saline-treated rats. This inhibitor at concentrations of 0.5 and 1 microM enhanced both the MCF and percent phagocytosis of AMs from LPS-challenged rats. Calyculin A at a concentration of 10 nM increased the MCF phagocytosis of AMs from LPS-challenged rats. At higher concentrations (20 and 30 nM), calyculin A showed a suppression on both the MCF and percent phagocytosis of AMs in both saline and LPS groups. AM CD18 expression was not altered following LPS challenge. Phosphatase inhibitors at doses that enhanced AM phagocytosis showed either no effect (okadaic acid) or inhibition (calyculin A) of AM CD18 expression. These results suggest that ser/thr phosphorylation and dephosphorylation participate in mediating the phagocytic response of AMs to LPS.
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PMID:Serine/threonine phosphorylation in cellular signaling for alveolar macrophage phagocytic response to endotoxin. 1063 67

Selenium, an essential biological trace element, has been shown to modulate functions of many regulatory proteins involved in signal transduction and to affect a variety of cellular activities including cell growth, survival, and death. The molecular mechanism by which selenium exerts its action on the cellular events, however, remains unclear. In our present study, we observed that selenite suppresses both the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase pathway in 293T cells. In contrast, selenite had little effect on the extracellular signal-regulated kinase pathway. Furthermore, selenite directly inhibited JNK/SAPK activity in vitro but not the p38 activity. The in vitro inhibition of JNK/SAPK by selenite was reversed by the addition of reducing agents such as dithiothreitol and beta-mercaptoethanol. Replacement of cysteine 116 in JNK1 by serine abolished the inhibitory effect of selenite on JNK1 activity both in vitro and in vivo. Selenite also suppressed a c-Jun-dependent luciferase reporter activity stimulated through the JNK signaling pathway. Taken together, our findings strongly suggest that selenite differentially modulates the mammalian mitogen-activated protein kinase pathways and that it can repress the JNK/SAPK signaling pathway by inhibiting JNK/SAPK through a thiol redox mechanism.
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PMID:Selenite inhibits the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) through a thiol redox mechanism. 1064 9


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