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)

p202, an interferon-inducible murine protein, is a member of the "200 family" of proteins and is primarily nuclear. p202 is a modulator of transcription; it binds several transcription factors, including NF-kappaB p50 and p65, AP-1 c-Fos and c-Jun, and E2F1, and inhibits their transcriptional activity. p202 also binds pRb, the retinoblastoma protein, and if overexpressed it retards cell proliferation. Here we report that using the yeast two-hybrid assay we found that p202 bound the murine homolog of the human p53-binding protein 1 (53BP1), a protein shown to interact with the DNA binding domain of the p53 tumor suppressor protein. p202 bound a 98amino acid segment from 53BP1. This binding was inhibited by the replacement in p202 of a histidine (from the M(F/L)HATVA(T/S) sequence that is conserved among all of the 200 family proteins) by phenylalanine. We also report that overexpression of p202 inhibited the p53-dependent expression of reporter genes containing p53-activable segments from the mdm2 and p21 genes, whereas a decrease in the p202 level (in consequence of the expression of 202 antisense RNA) resulted in an increase in the p53-dependent expression of these reporters. Expression of the 53BP1 segment binding to p202 overcame the inhibition by overexpressed p202 of the transcription of reporters mediated by the p53 or the AP-1 transcription factors and of the proliferation of yeast.
 ...
PMID:p202, an interferon-inducible modulator of transcription, inhibits transcriptional activation by the p53 tumor suppressor protein, and a segment from the p53-binding protein 1 that binds to p202 overcomes this inhibition. 891 Mar 40

p202a is a murine protein that is induced during the fusion of myoblasts to myotubes and can also be induced by interferon. Even 2-3-fold overexpression of p202a in cells retards proliferation. p202a was shown to modulate transcription by binding, and inhibiting the activity of several transcription factors including c-Fos, c-Jun, AP-2, E2F1, E2F4, NF-kappaB, MyoD, and myogenin. Here we report that p202a also bound the c-Myc protein in vitro and in vivo; the C-terminal p202a b segment bound the C-terminal basic region helix-loop-helix-leucine zipper (bHLHLZ) region of c-Myc. The transfection of a p202a expression plasmid inhibited the c-Myc-dependent expression of reporter plasmids in transient assays; moreover, overexpression of p202a in stable cell lines decreased the endogenous levels of mRNAs whose expression is driven by c-Myc. These effects of p202a are consistent with our finding that the binding of p202a to c-Myc inhibited the binding of c-Myc to Max in vitro and in vivo. p202a also inhibited the c-Myc-induced anchorage-independent growth and apoptosis of Rat-1 cells. The inhibition of c-Myc-dependent transcription, proliferation, and apoptosis by p202a is in line with the involvement of p202a in differentiation.
 ...
PMID:The interferon- and differentiation-inducible p202a protein inhibits the transcriptional activity of c-Myc by blocking its association with Max. 1083 25

There is increasing evidence that some neuronal death after brain ischaemia is mediated by the action of cysteine-requiring aspartate-directed proteases (caspases), the proteases responsible for apoptosis in mammals, although this form of neuronal death is not always accompanied by the morphological changes that are typical of apoptosis in other tissues. Caspase-mediated neuronal death is more extensive after transient than permanent focal brain ischaemia and may contribute to delayed loss of neurons from the penumbral region of infarcts. The activation of caspases after brain ischaemia is largely consequent on the translocation of Bax, Bak, and other BH3-only members of the Bcl-2 family to the mitochondrial outer membrane and the release of cytochrome c, procaspase-9, and apoptosis activating factor-1 (Apaf-1) from the mitochondrial intermembrane space. How exactly ischaemia induces this translocation is still poorly understood. NF-kappaB, the c-jun N-terminal kinase-c-Jun pathway, p53, E2F1, and other transcription factors are probably all involved in regulating the expression of BH3-only proteins after brain ischaemia, and mitochondrial translocation of Bad from sequestering cytosolic proteins is promoted by inactivation of the serine-threonine kinase, Akt. Other processes that are probably involved in the activation of caspases after brain ischaemia include the mitochondrial release of the second mitochondrial activator of caspases (Smac) or direct inhibitor-of-apoptosis-binding protein with low pI (DIABLO), the accumulation of products of lipid peroxidation, a marked reduction in protein synthesis, and the aberrant reentry of neurons into the cell cycle. Non-caspase-mediated neuronal apoptosis may also occur, but there is little evidence to date that this makes a significant contribution to brain damage after ischaemia. The intracellular processes that contribute to caspase-mediated neuronal death after ischaemia are all potential targets for therapy. However, anti-apoptotic interventions in stroke patients will require detailed evaluation using a range of outcome measures, as some such interventions seem simply to delay neuronal death and others to preserve neurons but not neuronal function.
 ...
PMID:Apoptosis and brain ischaemia. 1265 66

p202a is a member of the interferon-inducible murine p200 family of proteins. These proteins share 1 or 2 partially conserved 200 amino acid segments of the a or the b type. The known biological activities of p202a include among others the regulation of muscle differentiation, cell proliferation, and apoptosis. These biological activities of p202a can be correlated with the inhibition of the activity of several transcription factors. Thus, the binding of p202a results in the inhibition of the sequence-specific binding to DNA of the c-Fos, c-Jun, E2F1, E2F4, MyoD, myogenin, and c-Myc transcription factors. This study concerns the mechanisms by which p202a inhibits the activity of NF-kappaB, a transcription factor involved among others in host defense, inflammation, immunity, and the apoptotic response. NF-kappaB consists of p50 and p65 subunits. We demonstrate that p202a can inhibit in vitro and in vivo the binding to DNA of p65 homodimers and p50/65 heterodimers, whereas it increases the binding of p50 homodimers. Thus p202a can impair NF-kappaB activity both by inhibiting the binding to DNA of the transcriptionally active p65 homodimers and p50/p65 heterodimers and by boosting the binding of the repressive p50 homodimers. p202a can bind p50 and p65 in vitro and in vivo, and p202a can be part of the p50 homodimer complex bound to DNA. p50 binds in p202a to the a type segment, whereas p65 binds to the b type segment. Transfected ectopic p202a increases the apoptotic effect of tumor necrosis factor (at least in part) by inhibiting NF-kappaB and its antiapoptotic activity.
 ...
PMID:The interferon-inducible p202a protein modulates NF-kappaB activity by inhibiting the binding to DNA of p50/p65 heterodimers and p65 homodimers while enhancing the binding of p50 homodimers. 1267 38

Alzheimer's disease (AD) is the major cause of dementia, accounting for 50% to 70% of the late-onset patients, with 17 to 20 million affected. It is characterized by neurofibrillary tangles, neuronal loss, and amyloid plaques in tissues of the cortex, hippocampus, and amygdala. Apoptosis or programmed cell death appears in the progression of AD. In this study, we investigated the gene expression of 14 apoptotic genes (E2F1, p21/WAF, ICE-LAP3, Fas Antigen, CPP-32, GADD153, ICE-beta, c-Fos, c-Jun, Bax-alpha, Bcl-2, Bcl-(x)L, BAK, and p53) in 5 normal and 6 AD human hippocampal tissues, using reverse transcription-polymerase chain reaction. Our results show an upregulation of gene expression in AD patients for c-Fos and BAK. ICE-beta, c-Jun, Bax-alpha, Bcl-x(L), p53, and GADD153 were found to be upregulated in some AD samples but were not detected or downregulated in other AD or normal samples. No gene expression was found for E2F1 , p21/WAF, ICE-LAP3, Fas Antigen, CPP32, or Bcl-2. These results indicate significant increases in c-Fos , c-Jun, and Bak; therefore, we suggest that these genes may be critical in the apoptotic cascades of AD.
 ...
PMID:Apoptotic gene expression in Alzheimer's disease hippocampal tissue. 1771 63

We analyzed in detail the proximal promoter of transcription factor Sp3, which expands 281 bp from the translational start. This sequence contains putative binding sites for Sp1, NF-Y, NF-1, Myb, AP-1 and E2F transcription factors. In this work, we further explored the role of these boxes on the regulation of the Sp3 gene. Gel-shift and competition assays showed specific binding of NF-1, Myb, AP-1 and E2F. Furthermore, chromatin immunoprecipitation assays demonstrated that Sp1, Sp3, NF-Y, NF-1, c-Myb, B-Myb, c-Jun and E2F1 actually occupied the Sp3 promoter in HeLa cells. Transient transfections and luciferase assays revealed activation of the Sp3 proximal promoter upon overexpression of NF-1, c-Myb, B-Myb, c-Jun and c-Fos, and repression after overexpression of E2F/DP1. Point mutation of the binding sites for NF1, Myb, AP1 and E2F and cell incubation with specific siRNAs further confirmed the role of these transcription factors in the regulation of the Sp3 promoter. The regulation of the endogenous Sp3 gene was also observed at the mRNA level when the studied transcription factors were overexpressed or knocked down by siRNA incubation. These results help to explain the complex regulation of the Sp3 gene, which depends, at least in part, on the relative amount of Sp1, Sp3, NF-Y, NF-1, c-Myb, B-Myb, AP-1, and E2F proteins in the cell.
 ...
PMID:Transcriptional regulation of the 5'-flanking region of the human transcription factor Sp3 gene by NF-1, c-Myb, B-Myb, AP-1 and E2F. 1834 22

Benzo(a)pyrene (B(a)P) is a potent lung carcinogen mainly derived from tobacco smoking and environmental contamination, however, the molecular mechanisms by which it accelerates the cell cycle progression and induces the abnormal cell proliferation are still far away from understood. Our current analysis of human embryo lung fibroblasts (HELF) showed that B(a)P exposure was able to promote cell cycle G(1)-S phase transition. This effect was correlated with c-Jun activation because inhibition of c-Jun by its dominant negative mutant (TAM67) reversed B(a)P action on cell cycle with the down-regulation of expression of cyclin D1, pRb and E2F1. Further study found that overexpression of dominant negative mutants of, PI-3K or Akt, dramatically reduced B(a)P-induced the activation of c-Jun and extracellular signaling regulated kinase (ERK), but not c-Jun NH2 terminal kinase (JNK). Inhibition of p53 by either its inhibitor pifithrin-alpha or p53 siRNA markedly increased B(a)P-induced the activation of c-Jun, Akt and ERK in this context. Take together, our results indicate that c-Jun activation by p53-dependent PI-3K/Akt/ERK pathway is responsible for B(a)P-induced cell cycle alternations in human embryo lung fibroblasts.
 ...
PMID:Benzo(a)pyrene-caused increased G1-S transition requires the activation of c-Jun through p53-dependent PI-3K/Akt/ERK pathway in human embryo lung fibroblasts. 1844 77

The transcription factor CCAAT enhancer-binding protein alpha (C/EBPalpha) has an important role in granulopoiesis. The tumor suppressor function of C/EBPalpha is shown by the findings that loss of expression or function of C/EBPalpha in leukemic blasts contributes to a block in myeloid cell differentiation and to leukemia. C/EBPalpha mutations are found in around 9% of acute myeloid leukemia (AML) patients. The mechanism by which the mutant form of C/EBPalpha (C/EBPalpha-p30) exerts a differentiation block is not well understood. By using a proteomic screen, we have recently reported PIN1 as a target of C/EBPalpha-p30 in AML. In the present study, we show that C/EBPalpha-p30 induces PIN1 expression. We observed elevated PIN1 expression in leukemic patient samples. Induction of C/EBPalpha-p30 results in recruitment of E2F1 in the PIN1 promoter. We show that the inhibition of PIN1 leads to myeloid differentiation in primary AML blasts with C/EBPalpha mutations. Overexpression of PIN1 in myeloid cells leads to block of granulocyte differentiation. We also show that PIN1 increases the stability of the c-Jun protein by inhibiting c-Jun ubiquitination, and c-Jun blocks granulocyte differentiation mediated by C/EBPalpha. Our data suggest that the inhibition of PIN1 could be a potential strategy of treating AML patients with C/EBPalpha mutation.
 ...
PMID:Elevated PIN1 expression by C/EBPalpha-p30 blocks C/EBPalpha-induced granulocytic differentiation through c-Jun in AML. 2037 80

The oligonucleotide Dz13 is a DNA enzyme (deoxyribozyme) that cleaves c-Jun mRNA. It has efficacious effects against tumors directly, is active against tumor-induced angiogenesis, inhibits neointima formation after arterial injury, and controls inflammatory responses. The off-target effects of Dz13 may in fact be driving some of these potentially therapeutic effects, though no mechanisms have been clearly defined in target cells. To this end, we here show that when a panel of human tumor cells that naturally propagate in bone are challenged with Dz13, the tumor suppressor E2F1 is upregulated regardless of cellular p53 status. The piddosomal components, p53-induced protein with a death domain and caspase-2, were translocated to the nucleus when deoxyribozymes were incubated with cells, but RIP associated Ich-1/CED homologous protein with death domain levels increased throughout the cell with either Dz13 or its scrambled control oligonucleotide. In response to Dz13-mediated cytotoxicity, cells upregulated levels of ERK, Akt, and p38. Summarily, these results suggest a cytotoxic stress (resembling DNA damage) response of tumor cells to Dz13, which induces apoptosis via the activation of inhibitor of caspase-activated deoxyribonuclease and protein kinase C delta. In vivo, in tumor-in-bone orthotopic and clinically relevant models for prostate and breast cancer metastasis, and a novel spontaneously metastasizing model for osteosarcoma (OS), Dz13 decreased growth in bone, and also metastasis for OS. This new model for OS was assessed to be clinically relevant in its expression of typical bone markers, osteopontin and osteocalcin. These results provide an off-target mechanism for Dz13 function, but this may be useful therapeutically against tumors.
 ...
PMID:Dz13 induces a cytotoxic stress response with upregulation of E2F1 in tumor cells metastasizing to or from bone. 2040 96

Lactoferrin (Lf) has been shown to control the proliferation of a variety of mammalian cells. Recently, we reported that human Lf induces apoptosis via a c-Jun N-terminal kinases (JNK)-associated Bcl-2 pathway that stimulates programmed cell death. In order to gain insight into the mechanism underlying Lf-triggered apoptotic features, we attempted to determine the mechanisms whereby the Lf-induced Bcl-2 family proteins exert their pro- or anti-apoptotic effects in Jurkat leukemia T lymphocytes. Treatment of the cells with high concentrations of Lf resulted in a significant reduction in in vitro growth and cell viability. As the levels of Lf increased, greater quantities of CDK6 and hyper-phosphorylated retinoblastoma protein were produced, resulting in the induction of E2F1-dependent apoptosis. Simultaneously, PARP and caspases were efficiently cleaved during Lf-induced apoptosis. The E2F1-induced apoptotic process occurred preferentially in p53-deficient Jurkat leukemia cells. Therefore, we attempted to determine whether E2F1-regulated Bcl-2 family proteins involved in the apoptotic process were relevant to Lf-induced apoptosis. We found that Lf increased the interaction of Bcl-2 with the pro-apoptotic protein Bad, whereas the total protein levels did not change significantly. Our results, collectively, suggest that Lf exploits the control mechanism of E2F1-regulated target genes or Bcl-2 family gene networks involved in the apoptotic process in Jurkat human leukemia T lymphocytes.
 ...
PMID:E2F1-directed activation of Bcl-2 is correlated with lactoferrin-induced apoptosis in Jurkat leukemia T lymphocytes. 2041 1


1 2 Next >>