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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations between the leucines of the "leucine zipper" domain of Jun D can either decrease (Asn 301 to Ala) or increase (Thr 307, Ala 308, to Glu, Val) homodimer formation and specific binding to DNA even though such changes do not modify the predicted alpha-helical structure of this region. As shown previously, addition of Fos strongly increases the affinity of Jun for DNA by forming a heterodimer. The jun down mutation (Asn 301 to Ala) also diminishes DNA binding by the Fos-Jun D heterodimer. These data strongly support the coiled coil conformation of this region where residues adjacent to the leucines are also important for dimer formation. Ultraviolet cross-linking experiments have shown that both Fos and Jun directly contact the TGACTCA palindromic sequence defined as a TPA (12-O-tetradecanoyl phorbol-13-acetate) response element or TRE. Both Jun homodimers and Jun-Fos heterodimers bind this TRE as well as the cAMP responsive element (CRE or TGACGTCA) with comparable affinities. While strong c-Jun or Jun D binding requires a perfect palindrome, Jun-Fos complexes can also efficiently recognize sequences where the right half of the palindrome is less conserved (TGACTAA or TGACGCA).
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PMID:Jun DNA-binding is modulated by mutations between the leucines or by direct interaction of fos with the TGACTCA sequence. 256 20

The c-Fos and c-Jun proteins bind an AP1 site and activate transcription synergistically. These two proteins have a common activation domain which has two co-operating motifs, HOB1 and HOB2. The HOB1 motif of c-Jun includes S73 which is required for Ha-Ras-induced super-activation and phosphorylation by MAP kinase-like enzymes. Since c-Fos HOB1 has a conserved Thr residue (T232) analogous to c-Jun S73 we have proposed that c-Fos HOB1 will be regulated in the same way as c-Jun HOB1. Here we show that the HOB1-containing activation domain of c-Fos is stimulated by Ha-Ras in vivo and phosphorylated by a MAP kinase family member in vitro and that mutating T232 to Ala abolishes both functions. Collectively these results suggest that phosphorylation of the HOB1 motif increases its activation capacity. To provide direct evidence for this we change the context of c-Fos T232 to a PKA recognition site, and show that HOB1 activity is now stimulated by the catalytic subunit of PKA. This 'PKA specificity' experiment represents a novel and powerful way to analyse phosphorylation events involved in a variety of biological functions.
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PMID:Phosphorylation of the c-Fos and c-Jun HOB1 motif stimulates its activation capacity. 781 2

Treatment of cells with pro-inflammatory cytokines or ultraviolet radiation causes activation of the c-Jun NH2-terminal protein kinase (JNK). Activating transcription factor-2 (ATF2) was found to be a target of the JNK signal transduction pathway. ATF2 was phosphorylated by JNK on two closely spaced threonine residues within the NH2-terminal activation domain. The replacement of these phosphorylation sites with alanine inhibited the transcriptional activity of ATF2. These mutations also inhibited ATF2-stimulated gene expression mediated by the retinoblastoma (Rb) tumor suppressor and the adenovirus early region 1A (E1A) oncoprotein. Furthermore, expression of dominant-negative JNK inhibited ATF2 transcriptional activity. Together, these data demonstrate a role for the JNK signal transduction pathway in transcriptional responses mediated by ATF2.
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PMID:Transcription factor ATF2 regulation by the JNK signal transduction pathway. 782 38

Polyomavirus middle-sized tumor antigen (MT) increases the expression of c-jun through a phorbol 12-O-tetradecanoate 13-acetate response element in the c-jun promoter. To investigate the cellular signaling pathways affected by MT, we studied the role of the c-Ras and Raf-1 proteins in MT-induced transactivation of c-jun and cell transformation. There was an increase in GTP complexed to Ras in MT-expressing cells, indicating an increase in Ras activity. Coexpression of dominant inhibitory mutants of Ha-ras and raf-1 with MT inhibited MT-mediated transactivation and focus formation. Studies of the phosphorylation of c-Jun showed that MT expression increased the phosphorylation of Ser-63 and Ser-73 in the transactivation domain and decreased the phosphorylation of a peptide containing Ser-243, Ser-249, and Thr-231 in the DNA binding domain. MT increased the transcriptional activating ability of c-Jun but failed to increase the transcriptional activating ability of c-Jun mutants with Ser-63 and Ser-73 changed to nonphosphorylatable Ala, indicating that MT modulates c-Jun activity through phosphorylation. The dominant inhibitory mutants of Ha-ras and raf-1 interfered with the ability of MT to activate c-Jun. The results indicate that MT induces a phosphorylation cascade through the activation of c-Ras and Raf-1 and that c-Jun is one of the downstream targets that may cause changes in gene expression leading to cell transformation.
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PMID:Polyomavirus middle-sized tumor antigen modulates c-Jun phosphorylation and transcriptional activity. 793 38

Growth factors, phorbol esters, and oncogenes such as ras, src, and sis are believed to stimulate c-Jun transcriptional activation by inducing increased phosphorylation at two serine residues (S63 and S73) within the N-terminal transactivation domain. Although S63 and S73 are conserved in the mutant v-Jun oncoprotein, they are not phosphorylated by two enzymes which target the corresponding residues in c-Jun in vitro; namely a partially purified c-Jun kinase from TPA-stimulated U937 cells and purified p54 mitogen activated protein (MAP) kinase. In addition, v-Jun activates transcription more strongly than c-Jun when fused to the Gal4 DNA-binding domain, and transcriptional activation by Gal4-v-Jun is unaffected when S63, S73, or both, are replaced with non-phosphorylatable alanine residues, amino acid substitutions which severely impair transcriptional activation by Gal4-c-Jun. The novel biochemical and transcriptional properties of v-Jun result from deletion of a 27 amino acid segment, termed delta, which is important for transforming activity. On the basis of these results we propose that unlike c-Jun, v-Jun transcriptional activation is independent of positive regulatory phosphorylation and that this may contribute to oncogenesis by v-Jun.
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PMID:Transcriptional activation by the v-Jun oncoprotein is independent of positive regulatory phosphorylation. 803 19

C-Jun is a cellular transcription factor that can control gene expression in response to treatment of cells with phorbol esters, growth factors, and expression of some oncogenes. The ability of c-Jun to catalyze the transcription of certain genes is controlled, in part, by changes in the phosphorylation state of specific amino acids in c-Jun. One of the major sites that is phosphorylated during signal response is Ser73. Here we show that substitution of a negatively charged aspartic acid residue at 73 constitutively increased transcriptional activity of c-Jun. The Asp73 substitution also enhanced its availability to bind to DNA in a whole cell extract without altering its intrinsic DNA binding activity since the intrinsic activity was unaltered for the c-Jun mutant proteins expressed in a bacterial system. The negatively charged Asp substitution may mimic the negative charge of a phosphorylated serine at 73. The substitution of an uncharged alanine at 73 resulted in lowered activities. The N-terminal end of c-Jun containing these substitutions was fused to the DNA-binding region of the bovine papilloma virus E2 protein, and was able to confer the same activation properties to the fusion protein at the heterologous E2 DNA-binding site. Ser73 lies in a region of c-Jun previously proposed to bind an uncharacterized inhibitor, perhaps related to a protein of approximately 17.5 kD that coprecipitates along with our c-Jun or the JunE2 fusion products.
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PMID:Activation of c-Jun transcription factor by substitution of a charged residue in its N-terminal domain. 816 46

The transactivator protein of human T-lymphotropic virus type I (HTLV-I), Tax, forms multiprotein complexes with the ubiquitous transcription factor CREB and the CREB/ATF-1 heterodimer. The interaction between Tax and CREB is highly specific and results in increased binding of the Tax/CREB complexes to the HTLV-I 21-bp repeats. Despite the extensive sequence similarities between CREB and ATF-1, Tax interacts with ATF-1 only marginally. Compared with CREB, Tax/CREB exhibits greatly increased DNA recognition specificity and preferentially assembles on a consensus binding site, GGGGG(T/A)TGACG(T/C)(A/C)TA(T/C)C-CCCC, homologous to the HTLV-I 21-bp repeats. Here we report that Tax affects CREB binding to the Tax-inducible DNA elements by interacting with the basic-leucine zipper (bZip) domain of CREB. We show by domain switching that the basic region in CREB bZip can confer on c-Jun and ATF-1 leucine zippers the ability to interact with Tax in vitro. Mutational analyses further demonstrate that the amino acid residues of CREB critical for Tax/CREB interaction are Ala-Ala-Arg at positions 282-284 (AAR284), immediately upstream of the highly conserved DNA-binding domain (R/K)XX(R/K) N(R/K)XAAXX(S/C)RX(R/K)(K/R) characteristic of all bZip proteins. Specific amino acid substitutions in AAR284 of CREB weakened or abolished Tax/CREB interaction, whereas reciprocal changes in ATF-1 allowed it to interact with Tax. These results support a model in which the specific interaction between Tax and the AAR284 residues near the DNA-binding domain of CREB results in a multiprotein complex with altered DNA recognition property. This protein complex assembles selectively on the viral Tax-responsive 21-bp repeats to augment transcription.
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PMID:Expansion of CREB's DNA recognition specificity by Tax results from interaction with Ala-Ala-Arg at positions 282-284 near the conserved DNA-binding domain of CREB. 820 41

An Epstein-Barr virus-encoded protein, ZEBRA, mediates the switch from latency to the viral lytic life cycle. ZEBRA's domain structure and DNA binding specificity resemble that of cellular transcriptional activators such as c-Fos/c-Jun. We show that ZEBRA, like c-Jun, is phosphorylated by casein kinase II (CKII). The principal site of phosphorylation is serine-173 (S173), five amino acids upstream of the basic DNA recognition domain. CKII phosphorylation abrogated ZEBRA's capacity to bind its target DNA sequences. S173 is a functional component of ZEBRA's DNA binding domain, since mutation of S173 to alanine (S173A) reduced DNA binding in vitro to 10% of wild-type levels. Transcriptional activation of a native viral promoter in vivo by mutant S173A was also reduced markedly. Reversible phosphorylation of S173 is likely to be an important means of regulating ZEBRA's activity in vivo.
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PMID:Serine-173 of the Epstein-Barr virus ZEBRA protein is required for DNA binding and is a target for casein kinase II phosphorylation. 823 66

Triggering of CD95 (APO-1/Fas) on different T- and B-cell lines resulted in the induction of a number of kinases (35 kDa, 38 kDa, 46 kDa and 54 kDa) that phosphorylate c-Jun and to a lesser extent Histone H1. Activation of these kinases was independent of protein biosynthesis and preceded apoptotic DNA degradation. The kinase activation pattern was specific for CD95 triggering since a variety of physical or chemical inducers of T- and B-cell apoptosis activated different kinases. The kinase activities at 46 and 54 kDa contained members of the stress-activated family of protein kinases (JNK/SAPK). Activation of the CD95-specific set of kinases was prevented by treating cells with the ICE-inhibiting peptide N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) or by overexpression of the cow pox virus serpin CrmA. However, despite inhibition of ICE-like proteases the death signal was readily initiated at the cell membrane since a CD95 death-inducing signaling complex (DISC) was formed. Thus, our results demonstrate that ICE-like proteases in the CD95 pathway function downstream of the DISC but upstream of SAP kinases.
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PMID:CD95 (APO-1/Fas) induces activation of SAP kinases downstream of ICE-like proteases. 895 Sep 75

Transgenic mice carrying amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1 (SOD1) mutations develop a motoneuron disease resembling human ALS. c-Jun is a transcription factor frequently induced in injured neurons. In this study we have examined the distribution of c-Jun-immunoreactivity in the brainstem and spinal cord of transgenic SOD1 mice with a glycine 93 alanine (G93A) mutation. In non-transgenic littermates c-Jun immunostaining was predominantly situated in motoneurons. The number of c-Jun immunoreactive motoneuron was reduced in SOD1(G93A) mice due to pronounced loss of motoneurons. In SOD1(G93A) mice, however, c-Jun-immunoreactivity was strongly induced in neurons in the intermediate zone (Rexed's laminae V-VIII and X) of the spinal cord and throughout the brainstem reticular formation. These findings are of interest since increased levels of c-jun also have been found in the intermediate zone of the spinal cord of ALS patients. This c-Jun may be involved in the neurodegenerative processes both in ALS and in motoneuron disease in SOD1(G93A) mice.
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PMID:Induction of c-Jun immunoreactivity in spinal cord and brainstem neurons in a transgenic mouse model for amyotrophic lateral sclerosis. 897 9


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