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)

The transcriptional coactivators CREB-binding protein and p300 regulate inducible transcription in multiple cellular processes and during the establishment of inflammatory and immune response. Several viruses have been shown to interfere with CREB-binding protein/p300 function, modulating their transcriptional activity. In this study, we report that the viral protein A238L interacts with the amino-terminal region of p300, inhibiting the acetylation and transcriptional activation of NF-ATc2, NF-kappaB, and c-Jun in stimulated human T cells. We demonstrate that A238L modulates the autoacetylation of p300 without altering its intrinsic histone acetyl transferase activity. Furthermore, we show that the molecular mechanism of the inhibition executed by the viral protein is conducted through blocking protein kinase C (PKC)-p300 interaction and further acetylation in the amino-terminal transactivation domain of the coactivator, and that Ser(384), within the CH1 domain, is essential for the full transcriptional activation of the coactivator. Moreover, we show that overexpression of an active form of PKC-theta reverts the A238L-mediated inhibition of the transcriptional activity of p300, showing, for the first time, a PKC-theta-mediated up-regulation of the coactivator. These findings provide new strategies to develop therapies potentially useful in the control of disorders related to p300 deregulation.
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PMID:A238L inhibits NF-ATc2, NF-kappa B, and c-Jun activation through a novel mechanism involving protein kinase C-theta-mediated up-regulation of the amino-terminal transactivation domain of p300. 2566 78

Under neuropathological conditions, reactive astrocytes release cytokines and chemokines, which act in an autocrine and/or paracrine fashion to modulate production of immunoregulatory factors from cells including microglia, astrocytes, and neurons. In this way, astrocytes play an important role in orchestrating immune responses within the central nervous system (CNS). Suppressor of cytokine signaling (SOCS) proteins are endogenous, negative regulators of the JAK/STAT signaling pathway and function as attenuators of the immune and inflammatory responses. As such, SOCS proteins may have critical roles in the CNS under neuroinflammatory conditions. In the inflamed CNS, expression of IL-6 cytokine family member oncostatin M (OSM) is elevated; however, its functional effects are not well understood. We demonstrate that OSM is a potent inducer of SOCS-3 in astrocytes. Analysis of the SOCS-3 promoter revealed that an AP-1 element, two IFN-gamma activation sequence (GAS) elements, and a GC-rich region are crucial for SOCS-3 gene expression. Using small interfering RNA against STAT-3, as well as a STAT-3 dominant-negative construct, we demonstrate that STAT-3 activation is critical for OSM induction of SOCS-3 expression. The ERK1/2 and JNK pathways also contribute to OSM-induced SOCS-3 gene expression. OSM stimulation led to a time-dependent recruitment of the transcription factors STAT-3, c-Fos, c-Jun, and Sp1 and the coactivators CREB-binding protein (CBP) and p300 to the endogenous SOCS-3 promoter. These data indicate that OSM-induced activation of STAT-3 and the ERK1/2 and JNK pathways are critical for astrocytic expression of SOCS-3, which provides for feedback inhibition of cytokine-induced inflammatory responses in the CNS.
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PMID:Molecular basis of oncostatin M-induced SOCS-3 expression in astrocytes. 1857 93

The mechanism by which the histone deacetylase (HDAC) inhibitor trichostatin A inhibits epidermal growth factor (EGF)-induced human 12(S)-lipoxygenase expression was studied. Trichostatin A treatment of human epidermoid carcinoma A431 cells inhibited the EGF-induced 12(S)-lipoxygenase enzymatic activity in a dose-dependent manner that was consistent with the expression of 12(S)-lipoxygenase mRNA and protein. Confocal microscopy indicated that trichostatin A treatment of cells resulted in downregulation of EGF-induced c-Jun expression. Western blotting revealed that trichostatin A treatment of cells resulted in downregulation of EGF-induced c-Jun and constitutively Sp1 expression. Results of a chromatin immunoprecipitation assay revealed that trichostatin A treatment of cells also upregulated Sp1 acetylation and attenuated the recruitment of Sp1, c-Jun, and p300 to the 12(S)-lipoxygenase gene promoter. These results suggested that trichostatin A inhibited EGF-induced 12(S)-lipoxygenase expression by multiple mechanisms, including the attenuation of c-Jun and Sp1 expression and p300 recruitment to the 12(S)-lipoxygenase gene promoter.
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PMID:Attenuation of c-Jun and Sp1 expression and p300 recruitment to gene promoter confers the trichostatin A-induced inhibition of 12(S)-lipoxygenase expression in EGF-treated A431 cells. 1859 Jul 21

The local structural properties and spatial conformations of chromosomes are intimately associated with gene expression. The spatial associations of critical genomic elements in inducible nitric-oxide synthase (iNOS) transcription have not been previously examined. In this regard, the murine iNOS promoter contains 2 NF-kappaB binding sites (nt -86 and nt -972) that are essential for maximal transactivation of iNOS by LPS. Although AP-1 is commonly listed as an essential transcription factor for LPS-mediated iNOS transactivation, the relationship between AP-1 and NF-kappaB in this setting is not well studied. In this study using a model of LPS-stimulated ANA-1 murine macrophages, we demonstrate that short range DNA looping occurs at the iNOS promoter. This looping requires the presence of AP-1, c-Jun, NF-kappaB p65, and p300-associated acetyltransferase activity. The distal AP-1 binding site interacts via p300 with the proximal NF-kappaB binding site to create this DNA loop to participate in iNOS transcription. Other geographically distant AP-1 and NF-kappaB sites are certainly occupied, but selected sites are critical for iNOS transcription and the formation of the c-Jun, p65, and p300 transcriptional complex. In this "simplified" model of murine iNOS promoter, numerous transcription factors recognize and bind to various response elements, but these locales do not equally contribute to iNOS gene transcription.
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PMID:Characterization of short range DNA looping in endotoxin-mediated transcription of the murine inducible nitric-oxide synthase (iNOS) gene. 2810 16

Cytosolic phospholipase A2 (cPLA2) plays a pivotal role in mediating agonist-induced arachidonic acid release for prostaglandin (PG) synthesis during stimulation with interleukin-1beta (IL-1beta). However, the mechanisms underlying IL-1beta-induced cPLA2 expression and PGE2 synthesis by canine tracheal smooth muscle cells (CTSMCs) have not been defined. IL-1beta induced cPLA2 protein and mRNA expression, PGE2 production, and phosphorylation of p42/p44 MAPK, p38 MAPK (ATF2), and JNK (c-Jun) in a time- and concentration-dependent manner, determined by Western blotting, RT-PCR, and ELISA, which was attenuated by the inhibitors of MEK1/2 (U0126), p38 MAPK (SB202190), and JNK (SP600125), or transfection with dominant negative mutants of MEK1/2, p38, and JNK, respectively. Furthermore, IL-1beta-induced cPLA2 expression and PGE2 synthesis was inhibited by a selective NF-kappaB inhibitor (helenalin) or transfection with dominant negative mutants of NF-kappaB inducing kinase (NIK), IkappaB kinase (IKK)-alpha, and IKK-beta. Consistently, IL-1beta stimulated both IkappaB-alpha degradation and NF-kappaB translocation into nucleus in these cells. NF-kappaB translocation was blocked by helenalin, but not by U0126, SB202190, and SP600125. MAPKs together with NF-kappaB-activated p300 recruited to cPLA2 promoter thus facilitating the binding of NF-kappaB to cPLA2 promoter region and expression of cPLA2 mRNA. IL-1beta-induced cPLA2 expression and PGE2 production was inhibited by actinomycin D and cycloheximide, indicating the involvement of transcriptional and translational events in these responses. These results suggest that in CTSMCs, IL-1beta-induced cPLA2 expression and PGE2 synthesis was independently mediated through activation of MAPKs and NF-kappaB pathways and was connected to p300 recruitment and activation.
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PMID:Involvement of MAPKs, NF-kappaB and p300 co-activator in IL-1beta-induced cytosolic phospholipase A2 expression in canine tracheal smooth muscle cells. 1870 82

Up-regulation of c-Jun is a common event in the developing, adult as well as in injured nervous system that serves as a model of transcriptional control of brain function. Functional studies employing in vivo strategies using gene deletion, targeted expression of dominant negative isoforms and pharmacological inhibitors all suggest a three pronged role of c-Jun action, exercising control over neural cell death and degeneration, in gliosis and inflammation as well as in plasticity and repair. In vitro, structural and molecular studies reveal several non-overlapping activation cascades via N-terminal c-Jun phosphorylation at serine 63 and 73 (Ser63, Ser73), and threonine 91 and 93 (Thr91, Thr93) residues, the dephosphorylation at Thr239, the p300-mediated lysine acetylation of the near C-terminal region (Lys268, Lys271, Lys 273), as well as the Jun-independent activities of the Jun N-terminal family of serine/threonine kinases, that regulate the different and disparate cellular responses. A better understanding of these non-overlapping roles in vivo could considerably increase the potential of pharmacological agents to improve neurological outcome following trauma, neonatal encephalopathy and stroke, as well as in neurodegenerative disease.
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PMID:c-Jun expression, activation and function in neural cell death, inflammation and repair. 1879 28

An infamous poison, arsenic also has been used as a drug for nearly 2400 years; in recently years, arsenic has been effective in the treatment of acute promyelocytic leukemia. Increasing evidence suggests that opposite effects of arsenic trioxide (ATO) on tumors depend on its concentrations. For this reason, the mechanisms of action of the drug should be elucidated, and it should be used therapeutically only with extreme caution. Previously, we demonstrated the opposing effects of ERK1/2 and JNK on p21(WAF1/CIP1) (p21) expression in response to ATO in A431 cells. In addition, JNK phosphorylates c-Jun (Ser(63/73)) to recruit TGIF/HDAC1 to suppress p21 gene expression. Presently, we demonstrated that a high concentration of ATO sustains ERK1/2 phosphorylation, and increases c-Fos biosynthesis and stability, which enhances p21 gene expression. Using site-directed mutagenesis, a DNA affinity precipitation assay, and functional assays, we demonstrated that phosphorylation of the C-terminus of c-Fos (Thr(232), Thr(325), Thr(331), and Ser(374)) plays an important role in its binding to the p21 promoter, and in conjunction with N-terminus phosphorylation of c-Fos (Ser(70)) to transactivate p21 promoter expression. In conclusion, a high concentration of ATO can sustain ERK1/2 activation to enhance c-Fos expression, then dimerize with dephosphorylated c-Jun (Ser(63/73)) and recruit p300/CBP to the Sp1 sites (-84/-64) to activate p21 gene expression in A431 cells.
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PMID:Arsenic trioxide phosphorylates c-Fos to transactivate p21(WAF1/CIP1) expression. 1882 10

B cell chronic lymphocytic leukemia (B-CLL) is the most common human leukemia. Deregulation of the T cell leukemia/lymphoma 1 (TCL1) oncogene in mouse B cells causes a CD5-positive leukemia similar to aggressive human B-CLLs. To examine the mechanisms by which Tcl1 protein exerts oncogenic activity in B cells, we investigated the effect of Tcl1 expression on NF-kappaB and activator protein 1 (AP-1) activity. We found that Tcl1 physically interacts with c-Jun, JunB, and c-Fos and inhibits AP-1 transcriptional activity. Additionally, Tcl1 activates NF-kappaB by physically interacting with p300/CREB binding protein. We then sequenced the TCL1 gene in 600 B-CLL samples and found 2 heterozygous mutations: T38I and R52H. Importantly, both mutants showed gain of function as AP-1 inhibitors. The results indicate that Tcl1 overexpression causes B-CLL by directly enhancing NF-kappaB activity and inhibiting AP-1.
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PMID:Tcl1 functions as a transcriptional regulator and is directly involved in the pathogenesis of CLL. 1906 21

Activation transcription factor-2 (ATF-2) is phosphorylated by various protein kinases, such as JNK/p38/ERK, calmodulin kinase IV, protein kinase A, and protein kinase C (PKC), in response to a variety of stimuli. However, the role of the phosphorylation of ATF-2 by PKC in vivo in the transcriptional control of genes that include the activation protein-1 (AP-1)/cyclic AMP-response element remains to be defined. Using antibodies against the phosphorylated serine residue (Ser(P)) at position 121 of ATF-2, we have demonstrated that PKC phosphorylates ATF-2 at Ser-121 and that phosphorylation of Ser-121 (to yield ATF-2pS121) becomes detectable at the late stage of the response of HeLa cells to 12-O-tetradecanoylphorbol-13-acetate (TPA) and is maintained for more than 2 h. By contrast, phosphorylation of ATF-2 at threonine residues 69 and 71 (Thr-69/71, to yield ATF-2pT69/71) and at Ser-340 and Ser-367 (to yield ATF-2pS340 and ATF-2pS367) is detectable as an immediate early response. Unlike levels of ATF-2pT69/71 and ATF-2pS340, the level of ATF-2pS121 increases in the nuclei of HeLa cells in response to TPA. A serine-to-alanine mutation at position 121 of ATF-2 represses the c-Jun-dependent transcription of AP-1/cyclic AMP-response element reporter genes and also the p300-mediated activation of a Gal4-reporter gene in response to TPA. Our results suggest that the phosphorylation of ATF-2 at Ser-121 plays a key role in the c-Jun-mediated activation of transcription that occurs in response to TPA.
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PMID:Phosphorylation of Activation Transcription Factor-2 at Serine 121 by Protein Kinase C Controls c-Jun-mediated Activation of Transcription. 1917 25

Matrix metalloproteinase (MMP)-1 promotes ultraviolet (UV)-triggered long-term detrimental effects such as cancer formation and premature skin aging. Although histone modifications may play a crucial role in the transcriptional regulation of MMP-1, the relationship between UV-induced histone modification and MMP-1 expression is not completely understood. Here, we identify regulators of histone acetylation that may link UV-mediated DNA damage and MMP-1 induction by UV in cultured human dermal fibroblasts (HDFs) in vitro. UV irradiation of HDFs induced MMP-1 expression and increased the level of phosphorylation of H2AX (gamma-H2AX), p53 and the acetylation of histone H3 (acetyl-H3). Total histone deacetylase (HDAC) enzymatic activity was decreased by UV irradiation, while histone acetyltransferase (HAT) activity was increased. Suppression of p300 histone acetyltransferase (p300HAT) activity by the p300HAT inhibitor anacardic acid (AA) or by down-regulation of p300 by siRNA prevented UV-induced MMP-1 expression and inhibited UV-enhanced gamma-H2AX, p53 level, and acetyl-H3. Using chromatin immunoprecipitation assays, we observed that gamma-H2AX, p53, acetyl-H3, p300 and c-Jun were consistently recruited by UV to a distinct region (-2067/-1768) adjacent to the p300 binding site (-1858/-1845) in the MMP-1 promoter. In addition, these recruitments of gamma-H2AX, p53, acetyl-H3, p300 and c-Jun to the p300-2 site were significantly abrogated by post-treatment with AA. Furthermore, overexpression of p300 increased the basal and UV-induced MMP-1 promoter activity. Our results suggest that p300HAT plays a critical role in the transcriptional regulation of MMP-1 by UV.
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PMID:The role of p300 histone acetyltransferase in UV-induced histone modifications and MMP-1 gene transcription. 1928 85


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