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 mammalian UV response results in rapid and dramatic induction of c-jun. Induction of a protooncogene, normally involved in mitogenic responses, by a genotoxic agent that causes growth arrest seems paradoxical. We now provide an explanation for the role of c-Jun in the UV response of mouse fibroblasts. c-Jun is necessary for cell-cycle reentry of UV-irradiated cells, but does not participate in the response to ionizing radiation. Cells lacking c-Jun undergo prolonged cell-cycle arrest, but resist apoptosis, whereas cells that express c-Jun constitutively do not arrest and undergo apoptosis. This function of c-Jun is exerted through negative regulation of p53 association with the p21 promoter. Cells lacking c-Jun exhibit prolonged p21 induction, whereas constitutive c-Jun inhibits UV-mediated p21 induction.
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PMID:The mammalian UV response: c-Jun induction is required for exit from p53-imposed growth arrest. 1113 75

Heme is considered to play an instrumental role in the pathology of hemolysis, trauma, and reperfusion following ischemia. However, data are sparse and experimental models are required. The transport of heme by hemopexin to tissues is a specific, membrane receptor-mediated process. Hemopexin recycles after endocytosis like transferrin. Heme oxygenase-1 (HO-1), transferrin, the transferrin receptor, and ferritin are regulated by heme-hemopexin. Genes that encode proteins important for cellular defenses against oxidative stress, such as the cysteine-rich metallothioneins (MTs), are also activated by hemopexin, as are proteins that regulate cell cycle control including p21WAF1 and the tumor suppressor p53. The hemopexin system is being investigated to establish how intracellular events are affected by signal(s) from the plasma membrane due to hemopexin receptor occupancy and heme transport. A transient oxidative modification of proteins, shown by carbonyl production, takes place. Redox processes at the cell surface, which generate cuprous ions, are involved in the regulation of the MT-1 and HO-1 genes by heme-hemopexin before heme catabolism and intracellular release of iron. The "redox-sensitive" transcription factors activated by the hemopexin system include c- Jun, RelA/NFkappaB and MTF-1. The specific copper chelator bathocuproine disulfonate prevents carbonyl production, the nuclear translocation of MTF-1, and the induction of MT-1 revealing a novel, pivotal role for copper in the hemopexin system. In addition, surface redox-active copper is the first link shown for the concomitant regulation of HO-1 and MT-1 and is required for the activation of the amino-terminal c-Jun kinase (JNK) by heme-hemopexin.
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PMID:Links between cell-surface events involving redox-active copper and gene regulation in the hemopexin heme transport system. 1122 23

Resveratrol, a phytoalexin found in grapes, berries, and peanuts, is one of the most promising agents for cancer prevention. Our previous study showed that the antitumor activity of resveratrol occurs through p53-mediated apoptosis. In this study, we have elucidated the potential signaling components underlying resveratrol-induced p53 activation and induction of apoptosis. We found that in a mouse JB6 epidermal cell line, resveratrol activated extracellular-signal-regulated protein kinases (ERKs), c-Jun NH2-terminal kinases (JNKs), and p38 kinase and induced serine 15 phosphorylation of p53. Stable expression of a dominant negative mutant of ERK2 or p38 kinase or their respective inhibitor, PD98059 or SB202190, repressed the phosphorylation of p53 at serine 15. In contrast, overexpression of a dominant negative mutant of JNKI had no effect on the phosphorylation. Most importantly, ERKs and p38 kinase formed a complex with p53 after treatment with resveratrol. Strikingly, resveratrol-activated ERKs and p38 kinase, but not JNKs, phosphorylated p53 at serine 15 in vitro. Furthermore, pretreatment of the cells with PD98059 or SB202190 or stable expression of a dominant negative mutant of ERK2 or p38 kinase impaired resveratrol-induced p53-dependent transcriptional activity and apoptosis, whereas constitutively active MEK1 increased the transcriptional activity of p53. These data strongly suggest that both ERKs and p38 kinase mediate resveratrol-induced activation of p53 and apoptosis through phosphorylation of p53 at serine 15.
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PMID:Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. 1124 72

L-Thyroxine (T(4)) nongenomically promotes association of mitogen-activated protein kinase (MAPK) and thyroid hormone receptor TRbeta1 (TR) in the cell nucleus, leading to serine phosphorylation of the receptor. The oncogene suppressor protein, p53, is serine phosphorylated by several kinases and is known to interact with TRbeta1. We studied whether association of p53 and TR is modulated by T(4) and involves serine phosphorylation of p53 by MAPK. TR-replete 293T human kidney cells were incubated with a physiological concentration of T(4) for 10-90 min. Nuclear fractions were immunoprecipitated and the resulting proteins separated and immunoblotted for co-immunoprecipitated proteins. Activated MAPK immunoprecipitates of nuclei from T(4)-treated cells accumulated p53 in a time-dependent manner; T(4) and T(4)-agarose were more effective than T(3). T(4)-induced nuclear complexing of p53 and MAPK was inhibited by PD 98059 (PD) and U0126, two MAPK kinase (MEK) inhibitors, and was absent in cells treated with MEK antisense oligonucleotide and in dominant negative Ras cells. T(4) also caused nuclear co-immunoprecipitation of TRbeta1 and p53, an effect also inhibited by PD. Nuclear complexing of p53 and MAPK also occurred in HeLa cells, which lack functional TR. Constitutively activated MAPK caused phosphorylation of a recombinant p53-GST fusion protein in vitro; thus, p53 is a substrate for MAPK. An indicator of p53 transcriptional activity, accumulation of the immediate-early gene product, c-Jun, was inhibited by T(4). This T(4) effect was reversed by PD, indicating that the transcriptional activity of p53 was altered by T(4)-directed MAPK-p53 interaction.
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PMID:Thyroid hormone promotes serine phosphorylation of p53 by mitogen-activated protein kinase. 1125 98

Members of the AP-1 transcription factor family, especially c-Jun and c-Fos, have long been known to mediate critical steps in the cellular response to ultraviolet (UV) irradiation. We sought to examine whether two newly discovered members of the AP-1 family, JDP-1 and JDP-2, also participate in the mammalian UV response. Here we report that JDP-2, but not JDP-1, is transiently induced upon UV challenge and that elevated levels of JDP-2 increase cell survival following UV exposure. This protective function of JDP-2 appears to be mediated through repression of p53 expression at the transcriptional level, via a conserved atypical AP-1 site in the p53 promoter.
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PMID:AP-1 repressor protein JDP-2: inhibition of UV-mediated apoptosis through p53 down-regulation. 1128 7

When MCF-7 cells were incubated with 10 or 20 microM CdCl(2), p53 protein level increased after 18 h. Among serines in p53 protein immunoprecipitated from cells treated with CdCl(2), only Ser 15 was phosphorylated. No clear phosphorylation was found on Ser 6, 9, 20, 37, and 392. Accumulation of p53 protein phosphorylated at Ser 15 was also found after 18 h exposure. While phosphorylation of extracellular signal-regulated protein kinase, c-Jun NH2-terminal kinase and p38 was found in cells treated with CdCl(2), treatment with U0126, LL-Z1640-2, or SB203580 did not suppress Ser 15 phosphorylation. On the other hand, treatment with wortmannin or caffeine suppressed CdCl(2)-induced Ser 15 phosphorylation and accumulation of p53 protein. The present results showed that cadmium induces phosphorylation of p53 at Ser 15 in MCF-7 cells depending on phosphatidylinositol 3-kinase related kinases, but not on mitogen-activated protein kinases.
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PMID:Cadmium induces phosphorylation of p53 at serine 15 in MCF-7 cells. 1130 31

We have assessed several ataxia Telangiectasia mutated (ATM)-dependent functions in cells derived from ataxia telangiectasia patients, carrying either an ATM 5762ins137 splice site or a 7271T-->G missense mutation, with a less severe phenotype compared with the classical disorder. ATM kinase in vitro, from 5762ins137 cells, showed the same specific activity as ATM in normal cells, but the protein was present at low levels. In contrast, mutant ATM kinase activity in the 7271T-->G cells was only about 6% that of the activity in normal cells, although the level of mutant protein expressed was similar to normal cells. Phosphorylation of the DNA double strand break repair proteins Nbs1 and hMre11, following DNA damage, was observed in normal and 7271T-->G cells but was almost absent in both 5762ins137 and classical ataxia telangiectasia cells. The kinetics of p53 response was intermediate between normal and classical ataxia telangiectasia cells in both the 7271T-->G and 5762ins137 cells, but interestingly, c-Jun kinase activation following DNA damage was equally deficient in cell lines derived from all the ataxia telangiectasia patients. Our results indicate that levels of ATM kinase activity, but not induction of p53 or c-Jun kinase activity, in these cells correlate with the degree of neurological disorder in the patients.
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PMID:Residual ataxia telangiectasia mutated protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T-->G mutations, showing a less severe phenotype. 1138 71

Vinblastine is an important antitumor agent that induces G(2)-M arrest and subsequent apoptosis in a wide variety of cell lines, but the molecular mechanisms that link mitotic arrest and apoptosis are poorly understood. The AP-1 transcription factor has been implicated in many critical cellular processes, including apoptosis, and is a major target of the c-Jun NH(2)-terminal kinase signaling pathway that is activated by vinblastine and other microtubule inhibitors. In this study we sought to determine the role of c-Jun NH(2)-terminal kinase/AP-1 in the response of KB3 carcinoma cells to vinblastine. For this purpose, we generated KB3 cell lines that stably expressed the c-Jun dominant-negative deletional mutant TAM67, which lacks the NH(2)-terminal transactivation domain. KB3-TAM67 cell lines displayed normal growth kinetics and essentially unaltered basal AP-1 activity, but vinblastine-induced phosphorylation of c-Jun and activating transcription factor-2, and AP-1 activation, were strongly inhibited. KB3-TAM67 cell lines arrested normally at G(2)-M in response to vinblastine, but were significantly more resistant to the drug, exhibiting markedly delayed apoptosis and increased overall survival, relative to control cells. To investigate the underlying mechanisms, differential expression of apoptotic regulatory genes was monitored by immunoblot and cDNA microarray analysis. We found that vinblastine treatment caused down-regulation of p53 and its target p21 and up-regulation of tumor necrosis factor alpha, Bak, and several other genes in control but not in KB3-TAM67 cells, identifying these genes as putative targets of vinblastine-inducible AP-1. These results demonstrate that vinblastine-inducible AP-1 plays a destructive, proapoptotic role and may do so by regulating the expression of a specific subset of target genes that promotes efficient apoptotic cell death following mitotic arrest.
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PMID:The c-Jun NH(2)-terminal protein kinase/AP-1 pathway is required for efficient apoptosis induced by vinblastine. 1138 75

The tumor suppressor, p53, has been shown to transcriptionally activate or silence a number of target genes. As an activator, p53 relies on its specific consensus sequence within the promoter. It is not clear whether p53 requires a specific DNA binding site in its action as a gene repressor. This report demonstrates that the human BKB1R gene is a p53 target. Expression of p53 in transiently transfected SV40-transformed IMR90 cells strongly suppressed luciferase reporter activity driven by a 1.8 kb BKB1R promoter as well as its minigene. These down-regulations were p53 dose-dependent. p53 reduced both basal and induced promoter activities of the minigene. Expression of p53 abolished the inducibility of the minigene. Induction of endogenous p53 expression by etoposide also inhibited promoter activity and minigene inducibility. Replacing the region containing both the putative p53 binding site and the TATA-box with a basal adenovirus promoter in the 1.8 kb promoter construct did not prevent p53 from inhibiting BKB1R promoter activity. Thus suppression by p53 is not mediated by competition with the TATA-binding protein and is not through interaction with the putative p53-binding site. p53 also does not appear to suppress BKB1R gene expression through interaction with c-Jun which functions in the inducibility of this gene [Yang et al., 2001].
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PMID:p53 down-regulates human bradykinin B1 receptor gene expression. 1140 Jan 61

Human Papilloma Virus (HPV) is associated in most instances with cervical cancer. The HPV oncoproteins target P53 protein for degradation, leading to deregulation of cell cycle. We investigated whether stabilization of P53 in cervical cancer cells, by downregulating HPV transcription would restore the apoptotic ability of these cells. Our findings show that vitamin C downregulates the redox sensitive transcription factor AP-1 and decreases one of its transcription targets HPV E6, and stabilizes P53. This was associated with an increase in Bax and decrease in Bcl-2 and telomerase activity. Accumulation of P53 and its target gene bax then sensitized HeLa cells to cell-cycle arrest, cell death/apoptosis induced by cisplatin, and etoposide. Increasing drug sensitivity of cervical carcinoma cells by stabilizing P53 using vitamin C is a novel approach and has potential clinical relevance.
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PMID:Vitamin C augments chemotherapeutic response of cervical carcinoma HeLa cells by stabilizing P53. 1140 73


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