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 main feature of cellular senescence is cessation of cell proliferation. Protooncogene c-fos, which is required for the cell to enter into DNA synthesis, is repressed in senescent fibroblasts. Diminished expression of c-fos and impaired formation of AP-1, which is a complex of c-Fos and c-Jun proteins acting as a transcription factor, was found in lymphocytes derived from old (> 18 months) mice and stimulated with Con A. There were no differences in c-jun expression and formation of other transcription factors (AP-2 and AP-3) between lymphocytes isolated from old and young mice.
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PMID:Loss of transcription factor AP-1 DNA binding activity during lymphocyte aging in vivo. 142 49

The proteins Fos and Jun dimerize to constitute the transcription factor AP-1 which is known to respond to treatment with phorbol esters. AP-1 binds to 12-O-tetradecanoylphorbol-13-acetate-responsive elements (TREs) palindromic sequences. cAMP-responsive elements (CREs) are very similar to TREs and CRE-binding proteins are similar in structure to Fos and Jun. Thus, the two main signal transduction pathways have closely related nuclear effectors which could possibly overlap and/or cross-talk. The gene CRE modulator (CREM) encodes both antagonists and an activator of the cAMP transcriptional response by alternative splicing. In this report we show that CREM antagonists are able to block the transcriptional activation elicited by c-Jun. The mechanism by which this repression is obtained does not require heterodimerization between CREM and the Fos and/or Jun proteins. In contrast, we show that both CREM and CRE-binding proteins (CREB) are able to bind TREs and therefore compete with c-Jun for this site. Removal of the phosphorylation domain in CREM does not affect the down-regulatory function. We also show that c-Fos does not affect the inhibitory function of CREM on c-Jun and that the transcriptional activation elicited by the other members of the jun family (JunB, JunD, and v-Jun) is also down-regulated by CREM.
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PMID:Transcriptional cross-talk: nuclear factors CREM and CREB bind to AP-1 sites and inhibit activation by Jun. 142 97

Transcription factor AP-1 is constituted by the various products of the fos and jun proto-oncogene family members, which associate as dimers to bind with variable efficiency to 12-O-tetradecanoyl phorbol 13-acetate (TPA)-responsive promoter elements (TREs). We have recently shown that DNA binding of AP-1 is regulated by an inhibitory protein, IP-1, whose activity is modulated by phosphorylation. Here it is shown that although AP-1 has a very high affinity for its recognition sequence, its binding to the TRE can be quickly inhibited by the addition of IP-1. IP-1 is more active on AP-1 complexes formed during a shorter period of time. IP-1 activity is blocked by stimulation of the protein kinase C (PKC) signal transduction pathway, achieved by treating HeLa cells with phorbol esters or with a diacylglycerol analog. We observed an increase in AP-1-DNA binding after treatment of the cells with either the calcium ionophore A-23187 or dibutyryl cAMP; this could be ascribed to inhibition of IP-1 activity. A decreased IP-1 activity also correlates with the increase in AP-1-DNA binding after stimulating cells with serum. This suggests that IP-1 is an important target of the various signal transduction pathways. No effect on AP-1 and IP-1 was detected in cells transformed by Ki-ras or v-raf; nor could an effect of inhibition of protein synthesis be observed. We also analysed IP-1 regulation upon differentiation of P19 embryonal carcinoma cells by retinoic acid. We conclude that IP-1 regulation has a pivotal role in the final modulation of Fos-Jun by signal transduction pathways.
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PMID:AP-1 (Fos-Jun) regulation by IP-1: effect of signal transduction pathways and cell growth. 143 49

The ability of the c-Jun protein, the main component of the transcription factor AP1, to interact directly or indirectly with the RNA polymerase II-initiation complex to activate transcription was investigated by in vivo transcription interference ("squelching") experiments. Coexpression of a Jun mutant lacking its DNA binding domain strongly represses the activity of wild-type c-Jun. Repression depends on the presence of the transactivation domains (TADs), suggesting that a limiting factor interacting with the TADs is essential to link Jun and the components of the transcriptional machinery. The activity of this intermediary factor(s) is restricted to TADs characterized by an abundance of negatively charged amino acids, as demonstrated by the abilities of the TADs of JunB, GAL4, and VP16 to repress c-Jun activity. Depending on the presence of the TADs of Jun, we found physical interaction between Jun and a cluster of three proteins with molecular masses of 52, 53, and 54 kDa (p52/54). Association between Jun and p52/54 is strongly reduced in the presence of VP16, suggesting that the two proteins compete for binding to p52/54. Transcription factors containing a different type of TAD (e.g., GHF1, estrogen receptor, or serum response factor) fail to inhibit Jun activity, suggesting that these proteins act through a different mechanism. We consider the requirement of Jun to interact with p52/54 utilized by other transcription factors a new mechanism in the regulation of transcription of Jun-dependent target genes.
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PMID:A common intermediary factor (p52/54) recognizing "acidic blob"-type domains is required for transcriptional activation by the Jun proteins. 144 82

The DNA-binding activity of c-Jun expressed in eukaryotic cells was found to be markedly enhanced if the intracellular concentration of binding sites for this transcription factor was increased by cotransfection of specific plasmid DNA. Dephosphorylation experiments, phosphate mapping studies, and mutational analysis indicate that phosphorylation of a cluster of serine and threonine residues situated in close proximity to the DNA-binding domain is responsible for the observed adaptation of c-Jun activity to the intracellular concentration of accessible target sites.
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PMID:Phosphorylation state and DNA-binding activity of c-Jun depend on the intracellular concentration of binding sites. 145 48

The proto-oncogene products c-Fos and c-Jun heterodimerize through their leucine zippers to form the AP-1 transcription factor. The transcriptional activity of the heterodimer is regulated by signal-dependent phosphorylation and dephosphorylation events. The stability of c-Fos was found to also be controlled by intracellular signal transduction. In transient expression and in vitro degradation experiments, the stability of c-Fos was decreased when the protein was dimerized with phosphorylated c-Jun. c-Jun protein isolated from phorbol ester-induced cells did not target c-Fos for degradation, which suggests that c-Fos is transiently stabilized after stimulation of cell growth. v-Fos protein, the retroviral counterpart of c-Fos, was not susceptible to degradation targeted by c-Jun.
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PMID:Targeted degradation of c-Fos, but not v-Fos, by a phosphorylation-dependent signal on c-Jun. 147 Sep 18

c-Jun belongs to a family of proteins that require dimerization for activity. Dimerization occurs through a leucine-rich region near the carboxy terminus called the leucine zipper. Jun can form dimeric complexes with other Jun family as well as Fos family members. The relative proportion of these different dimeric complexes is determined by the relative abundance of each family member at a particular time. Overexpression of v-Jun or c-Jun alone will lead to cell transformation of chicken embryo fibroblasts, albeit with varying efficiencies. Upon overexpression, v-Jun or c-Jun presumably becomes the predominant AP-1 component in the cell. Theoretically, this should lead to a larger proportion of homodimers than heterodimers. It is not clear what role, if any, the other Jun and Fos family proteins play during cell transformation. We have examined the ability of Jun to induce cell transformation in chicken embryo fibroblasts in the absence of interaction with other Jun or Fos family proteins. To this end, we have constructed a chicken v-Jun mutant that is incapable of heterodimerization. This was accomplished by replacing the leucine zipper region of Jun with that of the yeast transcription factor GCN4. This chimeric protein, VJ-GLZ, retains all of the DNA binding and transcriptional activation domains of v-Jun. As expected, in vitro translated VJ-GLZ was found to be incapable of forming heterodimers with c-Fos, FosB, and JunD.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Heterodimerization with c-Fos is not required for cell transformation of chicken embryo fibroblasts by Jun. 147 69

Exposure of mammalian cells to DNA-damaging agents induces the ultraviolet (UV) response, involving transcription factor AP-1, composed of Jun and Fos proteins. We investigated the mechanism by which UV irradiation induces the c-jun gene. The earliest detectable step was activation of Src tyrosine kinases, followed by activation of Ha-Ras and Raf-1. The response to UV was blocked by tyrosine kinase inhibitors and dominant negative mutants of v-src, Ha-ras, and raf-1. This signaling cascade leads to increased phosphorylation of c-Jun on two serine residues that potentiate its activity. These results strongly suggest that the UV response is initiated at or near the plasma membrane rather than the nucleus. The response may be elicited by oxidative stress, because it is inhibited by elevation of intracellular glutathione. Using tyrosine kinase inhibitors, we demonstrate that the UV response has a protective function.
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PMID:The mammalian ultraviolet response is triggered by activation of Src tyrosine kinases. 147 46

Blood reperfusion after temporary liver ischemia induces the expression of heat shock genes and the synthesis of heat shock proteins (hsps), in particular hsp 70. Induction requires a certain duration of ischemia, suggesting that cell damage before reperfusion is essential for activation of heat shock genes. The expression of the hsp 70 gene is preceded by activation of the cellular protooncogenes c-fos and c-jun. However, the product of these genes, which is transcription factor AP-1, seems unnecessary for activation of the hsp 70 gene, which does not require the integrity of protein synthesis. Hsp genes seem to behave as "early response genes," enabling the cell to respond to emergency situations.
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PMID:Stress proteins and reperfusion stress in the liver. 148 45

The recent finding that neurotransmitters and drugs that affect neurotransmission have important influences on gene expression suggests that drug-induced alterations in gene expression may underlie many long-term effects of addictive drugs, for example, dependence and drug-seeking behaviors. These long-term adaptive responses to opiate drugs have been particularly difficult to understand at a mechanistic level. Data presented here indicate that the gene encoding the opioid precursor proenkephalin is highly regulated by neural activity, second-messenger pathways, and PKA. These observations raise the possibility that drugs of abuse (e.g., opiates acting through opiate receptors) may act at the genetic level to modulate the expression of endogenous opiates and that these effects may underlie one component of the brain's long-term adaptive response to exogenous opiates. The transgenic animals described above can be used to investigate opiate drug-induced changes in proenkephalin gene expression, allowing rapid analysis of changes in proenkephalin gene expression in highly restricted populations of neurons in a fashion previously impossible. In addition, by analyzing the effects of specific enhancer mutations on tissue-specific and transsynaptic regulation of proenkephalin expression, transgenic models will permit mechanistic investigations within the intact nervous system that cannot otherwise be undertaken. Investigation of mechanisms underlying this process requires the analysis of intracellular signaling pathways, responsive DNA regulatory elements, and the transcription factors transducing synaptic signals into gene regulation. In the studies described herein, we demonstrate that AP-1 complexes consisting of different Jun proteins differentially regulate proenkephalin transcription at the CRE-2 element. c-Jun constitutively activates proenkephalin transcription, whereas JunD activates in a fashion completely dependent on the activation of second-messenger pathways and the cAMP-dependent PKA. JunB alone has no effect on proenkephalin gene expression, yet this molecule effectively blocks activation mediated by JunD and, hence, may act as a repressor. These data are consistent with a model (figure 4) in which preexisting JunD mediates the rapid cAMP-dependent activation of the proenkephalin enhancer, whereas IEGs such as JunB or c-Fos mediate the protein synthesis-dependent inactivation. Because c-Jun activates proenkephalin transcription constitutively, induction of c-Jun may lead to a further and prolonged activation of proenkephalin gene expression. Hence, the ratio of c-Jun to JunB induction may determine whether proenkephalin is repressed or further activated.
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PMID:Regulation of opioid gene expression: a model to understand neural plasticity. 149 20


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