Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transport processes for larger organic solutes at the canalicular membrane are mainly driven by members of the superfamily of ATP-binding cassette (ABC) transporters. The functions of these transporters range from bile component secretion to xenobiotica and phase II-conjugate export. The transcriptional control of the expression of their respective genes differs, and this may be to guarantee tissue specificity, effective response to stress, or changes in substrate concentrations. Inside the nucleus, the concentration of competing and specifically activated transcription factors determines the transcriptional activation in transporter gene expression. Some transcription factors function as sensors for metabolites (LXR, FXR, CAR, SREBP, PPARs), xenobiotics (PPARs, PXR), oxidative stress (NF-kappa B, AP-1), or DNA damage (p53). Changes in their nuclear concentrations and activity will influence the transcription rates of the respective target genes that contain specific responsive elements in their 5'-promoter/enhancer DNA sequences. Until now little was known about the transcriptional control of most ABC transporter proteins. However, due to the enormous progress in molecular biology, many tools have become recently available to study and understand the "battle inside the nucleus" with respect to hepatic transporter gene expression.
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PMID:Transcriptional control of hepatocanalicular transporter gene expression. 1107 99

Reperfusion of ischemic myocardium results in apoptotic cell death and DNA fragmentation. Several transcription factors are known to regulate the apoptotic cell death. This study sought to examine the regulation of cardiomyocyte apoptosis by these transcription factors. Isolated working rat hearts were divided into six groups: control, 15 min ischemia, 60 min ischemia, 15 min ischemia followed by 2 h reperfusion, ischemic stress adaptation by subjecting the hearts to four cyclic episodes to 5 min ischemia, each followed by 10 min of reperfusion, and adaptation followed by 15 min ischemia and 2 h reperfusion. Redox-regulated transcription factors, NF kappa B and AP-1 and the expression of two anti- and pro-apoptotic genes, Bcl-2 and p53 were determined. The results demonstrated NF kappa B and AP-1 progressively and steadily increased as a function of the duration of ischemia. In the adapted heart, NF kappa B binding remained high while AP-1 binding was lowered to almost baseline value. The anti-oxidant gene, Bcl-2 was downregulated in the ischemic/reperfused heart, but upregulated in the preconditioned myocardium. Significant induction of the expression of p53 occurred after ischemia and reperfusion. Apoptotic cells were barely detected in the adapted myocardium which was subjected to the same ischemia/reperfusion protocol. The results demonstrate for the first time differential regulation of cardiomyocyte apoptosis by pro- and anti-apoptotic transcription factors and genes as a function of different durations of ischemia and reperfusion.
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PMID:Regulation of cardiomyocyte apoptosis by redox-sensitive transcription factors. 1108 56

Mammalian cells exhibit complex cellular responses to genotoxic stress, including cell cycle checkpoint, DNA repair, and apoptosis. Inactivation of these important biological events will result in genomic instability and cell transformation. It has been demonstrated that gene activation is a critical initial step during the cellular response to DNA damage. A number of investigations have shown that transcription factors are involved in the regulation of stress-inducible genes. These transcription factors include p53, c-Myc, and AP-1 (c-fos and c-jun). However, the role for the octamer-binding transcription factor Oct-1 in the DNA damage-activated response is unknown. In this report, we have presented the novel observation that the transcription factor Oct-1 is induced after cells are exposed to multiple DNA-damaging agents and therapeutic agents, including UV radiation, methylmethane sulfonate, ionizing radiation, etoposide, cisplatin, and camptothecin. The induction of the Oct-1 protein is mediated through a posttranscriptional mechanism and does not require the normal cellular function of the tumor suppressor p53, indicating that the Oct-1 protein, as a transcription factor, may play a role in p53-independent gene activation. In addition to increased protein level, the activity of Oct-1 DNA binding to its specific consensus sequence is also enhanced by DNA damage. Therefore, these results have implicated that the transcription factor Oct-1 might participate in cellular response to DNA damage, particularly in p53-independent gene activation.
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PMID:Activation of the transcription factor Oct-1 in response to DNA damage. 1110 83

JunD is the most broadly expressed member of the Jun family and the AP-1 transcription factor complex. Primary fibroblasts lacking JunD displayed p53-dependent growth arrest, upregulated p19(Arf) expression, and premature senescence. In contrast, immortalized cell lines lacking JunD showed increased proliferation and higher cyclinD1 levels. These properties are reminiscent of the effects of oncogenic Ras expression on primary and established cell cultures. Furthermore, JunD(-/-) fibroblasts exhibited increased p53-dependent apoptosis upon ultraviolet irradiation and were sensitive to the cytotoxic effects of TNF-alpha. The antiapoptotic role of JunD was confirmed using an in vivo model of TNF-mediated hepatitis. We propose that JunD protects cells from senescence, or apoptotic responses to stress stimuli, by acting as a modulator of the signaling pathways that link Ras to p53.
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PMID:JunD protects cells from p53-dependent senescence and apoptosis. 1110 50

Neoplastically transformed mouse and human keratinocytes elevate transactivation of both activator protein 1 (AP-1) and nuclear factor kappaB (NFkappaB) transcription factors. The present study addresses the question of whether elevated NFkappaB in addition to elevated AP-1-dependent gene expression is necessary for maintaining the tumor cell phenotype. When a tetracycline-regulatable dominant-negative c-jun (TAM67, having a truncated transactivation domain) was expressed in tumorigenic human keratinocytes, AP-1- and NFkappaB- but not p53-dependent reporter activity was inhibited by 40-60%. Tumor phenotype, as measured by anchorage-independent growth, was inhibited by 90%. Neither AP-1/NFkappaB activation nor expression of tumor phenotype was inhibited in TAM67-harboring keratinocytes under noninducing conditions. Electrophoretic mobility shift analysis showed that induction of TAM67 expression slightly increased AP-1- but reduced NFkappaB DNA-binding activity. Immunoprecipitation showed that TAM67 interacted in keratinocyte nuclei with NFkappaB p65, suggesting that inhibition of NFkappaB by TAM67 is mediated by direct protein-protein interactions, possibly producing decreased binding to DNA or inactivating p65. To analyze the putative effector genes that may be targeted by TAM67, expression of genes responsive to AP-1 or NFkappaB was measured by reverse transcriptase-polymerase chain reaction in TAM67 transfectants with or without TAM67 induction. Induction of TAM67 inhibited or reduced the expression of collagenase I, stromelysin I (AP-1 responsive), and interleukins 1 and 6 (NFkappaB responsive). These results indicate that genes controlled by NFkappaB and by AP-1 may be transformation-relevant targets of TAM67 and that TAM67 may inhibit NFkappaB activation through direct interaction with NFkappaB p65. Moreover, the findings provide proof for the principle of using inducible TAM67 as a gene therapy to suppress tumor phenotype in human carcinoma cells.
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PMID:Induced expression of dominant-negative c-jun downregulates NFkappaB and AP-1 target genes and suppresses tumor phenotype in human keratinocytes. 1110 61

TNFalpha is a primary cytokine responsible for inflammatory and immunosuppressive responses in skin. After UV-B irradiation of cultured human keratinocytes, we found that TNFalpha was released into the media, as monitored by ELISA, and was bound to cells, as observed by immunofluorescence microscopy. The release of TNFalpha into cell culture supernatant during the 24 h after UV-B irradiation was augmented by the addition of IL-1alpha to the cells. Further, we found this secretion was unaffected by rapamycin, and therefore independent of FRAP DNA-protein kinase mediated signal transduction. However, UV-B also induced expression of membrane-bound TNFalpha, and this was dependent on FRAP signaling. In wild type mice, TNFalpha bound to skin increased immediately after irradiation, declined at 6 h, and then rose again at 12 h before falling by 24 h. This pattern of induction was confirmed by RT-PCR of TNFalpha mRNA message in cultured epidermal cells. Induction of membrane-bound TNFalpha was also found in c-fos gene knockout mice deficient in the AP-1 transcription factor, suggesting that, although AP-1 containing c-fos signaling is required for some UV responses, AP-1 containing c-fos is not required for this TNFalpha activation. However, in homozygous p53 knockout mice the basal level of TNFalpha bound to the epidermis was greatly elevated without UV irradiation. This level declined and remained constant following irradiation. This implies that p53 directly or indirectly represses TNFalpha gene expression and that modification of p53 mRNA stability or phosphorylation of p53 protein after UV may be responsible for TNFalpha induction in the membrane. Overexpression of the immunosuppressive cytokine TNFalpha in this locale may contribute to the carcinogen-susceptibility of p53 knockout mice.
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PMID:Regulation of TNFalpha production and release in human and mouse keratinocytes and mouse skin after UV-B irradiation. 1113 30

Redox mechanims play important roles in replication of human immunodeficiency virus type 1 (HIV-1) and cellular susceptibility to apoptosis signals. Viral replication and accelerated turnover of CD4+ T cells occur throughout a prolonged asymptomatic phase in patients infected by HIV-1. Disease development is associated with steady loss of CD4+ T cells by apoptosis, increased rate of opportunistic infections and lymphoproliferative diseases, disruption of energy metabolism, and generalized wasting. Such pathological states are preceded by: (i) depletion of intracellular antioxidants, glutathione (GSH) and thioredoxin (TRX), (ii) increased reactive oxygen species (ROS) production, and (iii) changes in mitochondrial transmembrane potential (deltapsi(m)). Disruption of deltapsi(m) appears to be the point of no return in the effector phase of apoptosis. Viral proteins Tat, Nef, Vpr, protease, and gp120, have been implicated in initiation and/or intensification of oxidative stress and disruption of deltapsi(m). Redox-sensitive transcription factors, NF-kappaB, AP-1, and p53, support expression of viral genes and proinflammatory lymphokines. ROS regulate apoptosis signaling through Fas, tumor necrosis factor (TNF), and related cell death receptors, as well as the T-cell receptor. Oxidative stress in HIV-infected donors is accompanied by increased glucose utilization both on the cellular and organismal levels. Generation of GSH and TRX from their corresponding oxidized forms is dependent on NADPH provided through the pentose phosphate pathway of glucose metabolism. This article seeks to delineate the genetic and metabolic bases of HIV-induced oxidative stress. Such understanding should lead to development of effective antioxidant therapies in HIV disease.
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PMID:Genetic and metabolic control of the mitochondrial transmembrane potential and reactive oxygen intermediate production in HIV disease. 1122 68

Thioredoxin (TRX) is a 12 kD protein with redox-active dithiol in the active site; -Cys-Gly-Pro-Cys-. We originally cloned human TRX as adult T cell leukemia derived factor (ADF) produced by HTLV-I transformed cells. TRX and related molecules maintain a cellular reducing enviroment, working in concert with the glutathione system. Physiologically, TRX has cytoprotective effects against oxidative stress. TRX promotes DNA binding of transcription factors such as NF-kB, AP-1, p53, and PEBP-2. The TRX superfamily, including thioredoxin-2 (mitochondrial thioredoxin) and glutaredoxin, are involved in biologically important phenomena via the redox-regulating system. Thioredoxin-binding protein-2, which we recently identified by a yeast two-hybrid system, is a type of endogenous modulator of TRX activity. TRX is secreted from the cells and exhibits cytokine-like and chemokine-like activities. Redox regulation by TRX plays a crucial role in biological responses against oxidative stress.
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PMID:Redox regulation by thioredoxin superfamily; protection against oxidative stress and aging. 1123 6

There is growing evidence which suggests that dysregulation of apoptosis may lead to several disease states including cancer. To investigate the mechanism controlling the induction of cell death, apoptosis defective/resistant (Apt-) mutants were isolated and characterized in this study. FDC-P1, a mouse myeloid cell line that depends upon IL-3 for survival and growth but undergoes apoptosis when deprived of growth factor, was mutagenized by treatment with ethyl methane sulfonate. We selected cells that survived the growth factor deprivation but did not grow without the factor. Surviving cells were cloned by limiting dilution and four clones that showed the least morphological characteristics and biochemical changes of apoptosis were chosen. Unlike the parent FDC-P1, these mutants were cross resistant to apoptosis induced by a variety of antitumor drugs such as Adriamycin, Dexamethasone, VP-16, as well as reactive oxygen species (ROS) generated by xanthine/xanthine oxidase (X/XO). We used one of these Apt- mutant to test candidate death genes. Our findings suggest that the preferential increase in Bax/Bcl-2 ratio, p53, c-Myc, Caspase-3 and decrease in AP-1 on treatment with various anticancer drugs may contribute to the preferential apoptotic response in FDC-P1 cells but to varying degrees. Whereas, the higher constitutive level of antioxidant enzymes superoxide dismutase and catalase in the Apt- mutant may contribute at least in part to its resistance.
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PMID:Differential sensitivity of murine myeloid FDC-P1 cells and apoptosis resistant mutant(s) to anticancer drugs. 1123 67

Infection with high-risk human papillomaviruses (HPV) is a major risk factor for development of cervical cancer. Expression of the HPV E6 and E7 oncoproteins increases in differentiating keratinocytes, resulting in inactivation of the p53 and retinoblastoma proteins, two important transcriptional regulators. We used cDNA microarrays to examine global alterations in gene expression in differentiating cervical keratinocytes after infection with retroviruses encoding HPV type 16 (HPV-16) E6 and E7. Expression of 80 cellular genes (approximately 4% of the genes on the array) was altered reproducibly by E6 and/or E7. Cluster analysis classified these genes into three functional groups: (i) interferon (IFN)-responsive genes, (ii) genes stimulated by NF-kappaB, and (iii) genes regulated in cell cycle progression and DNA synthesis. HPV-16 E6 or a dominant negative p53 protein downregulated multiple IFN-responsive genes. E6 decreased expression of IFN-alpha and -beta, downregulated nuclear STAT-1 protein, and decreased binding of STAT-1 to the IFN-stimulated response element. E7 alone was less effective; however, coexpression of E6 and E7 downregulated IFN-responsive genes more efficiently than E6. The HPV-16 E6 protein also stimulated expression of multiple genes known to be inducible by NF-kappaB and AP-1. E6 enhanced expression of functional components of the NF-kappaB signal pathway, including p50, NIK, and TRAF-interacting protein, and increased binding to NF-kappaB and AP-1 DNA consensus binding sites. Secretion of interleukin-8, RANTES, macrophage inflammatory protein 1alpha, and 10-kappaDa IFN-gamma-inducible protein were increased in differentiating keratinocytes by E6. Thus, high-level expression of the HPV-16 E6 protein in differentiating keratinocytes directly alters expression of genes that influence host resistance to infection and immune function.
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PMID:Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF-kappaB-responsive genes in cervical keratinocytes. 1128 78


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