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)

E1A oncogene expression sensitizes mammalian cells to apoptosis triggered by cytolytic lymphocytes (CL) [16]. Most studies suggest that E1A-induced apoptosis involves a p53-dependent cellular pathway that is blocked by the E1B 19 kDa gene product. In this study, the roles of p53 and E1B 19 kDa were tested for E1A sensitization to CL-induced apoptosis in contrast with apoptosis triggered by TNF alpha or chemical injuries. E1A sensitization to immune-mediated (CL- or TNF-induced) apoptosis was independent of p53 expression and was resistant to blockade by E1B 19 kDa protein in mouse and hamster cells. In contrast, the p53 requirement for chemically induced apoptosis of E1A-sensitized cells varied with the agent used to treat cells. Apoptosis induced by diverse chemical agents (hygromycin, beauvericin, etoposide, H(2)O(2)) was blocked by E1B 19 kDa expression. Therefore, both the p53-dependence and the E1B 19 kDa blockade of E1A-induced cellular sensitization to apoptotic injury depend on the type of proapoptotic injury tested. These data suggest that the mechanisms by which E1A sensitizes tumor cells to immune-mediated apoptosis and to rejection by immunocompetent animals do not require cellular expression of wild-type p53 and can function independently of the Bcl-2-like, antiapoptotic mechanisms of E1B 19 kDa.
 ...
PMID:E1A oncogene-induced cellular sensitization to immune-mediated apoptosis is independent of p53 and resistant to blockade by E1B 19 kDa protein. 1050 12

The hormonally active form of vitamin D3, 1,25-dihydroxyvitamin D3, and its two analogues, EB 1089 and CB 1093, are novel putative anticancer agents with an interesting profile of induction of growth inhibition, differentiation, and apoptosis in tumor cells. To study the signaling pathways mediating these events, we used two human breast cancer cell lines: MCF-7 cells, expressing a wild-type p53 tumor suppressor protein, and T47D cells, lacking a functional p53. Vitamin D compounds induced a growth arrest followed by apoptosis in both cell lines at concentrations ranging from 1 to 100 nM, indicating that p53 is not necessary for growth-inhibitory effects induced by vitamin D compounds. Surprisingly, apoptosis induced by these compounds occurred also independently of known caspases. Inhibition of caspase activation by overexpression of a cowpox-derived caspase inhibitor CrmA or by addition of inhibitory peptides acetyl-Asp-Glu-Val-Asp-aldehyde (200 microM), acetyl-Ile-Glu-Thr-Asp-aldehyde (50 microM), and Z-Val-Ala-D,L-Asp-fluoromethylketone (1 microM) showed no effect on the induction of growth arrest or apoptosis by vitamin D compounds under assay conditions in which apoptosis induced by TNF or staurosporine was effectively inhibited. Moreover, overexpression of caspase-3 in MCF-7 cells had no sensitizing effect to vitamin D compounds, and neither caspase-3-like protease activity nor cleavage of a caspase substrate poly(ADP)ribose polymerase was detected in lysates from apoptotic cells following the treatment with these compounds. Contrary to CrmA, overexpression of an antiapoptotic protein Bcl-2 in MCF-7 cells conferred a nearly complete protection from apoptosis induced by vitamin D compounds. Taken together, these data indicate that vitamin D compounds induce apoptosis via a novel caspase- and p53-independent pathway that can be inhibited by Bcl-2. This may prove useful in the treatment of tumors that are resistant to therapeutic agents that are dependent on the activation of p53 and/or caspases.
 ...
PMID:Apoptosis induced by vitamin D compounds in breast cancer cells is inhibited by Bcl-2 but does not involve known caspases or p53. 1051 95

HPV-16 E6 and E7 oncoproteins impair the cell cycle in human uterine cervix carcinoma cells (HUCC) by acting on p53 and retinoblastoma proteins, respectively. We recently reported that E7 related into the extracellular compartment by HUCC SiHa cells could inhibit immune T-cell response to recall and alloantigens by a mechanism involving an overproduction of the immunosuppressive IFN alpha by antigen presenting cells (APCs). In this study, we found that besides E7, E6 protein and the vascular endothelium growth factor (VEGF) were released into the SiHa cell supernatants, and we further showed that extracellular E7 but not E6 oncoprotein 1) inhibits the immune cell response to recall and alloantigens, and 2) enhances the release of angiogenic cytokines, including TNF alpha, IL-1 beta and IL-6 by macrophages and/or dendritic cells. VEGF unexpectedly released by cancer cells could also contribute to angiogenesis. Thus in HUCC the same E7 oncoprotein which contributes to controlling the cancer cell cycle has the means in its extracellular configuration to contribute to microenvironmental immunosuppressive and angiogenic processes. Neutralizing anti-E7 antibodies either passively administered or induced by active immunization could represent a new immunotherapeutic endeavour to combat the immunosuppression and/or neoangiogenesis effects of extracellular E7 protein.
 ...
PMID:HPV-16 E7 but not E6 oncogenic protein triggers both cellular immunosuppression and angiogenic processes. 1055 78

We have shown that the loss of p53 function contributed to resistance of tumor cells to TNF-induced cytotoxicity. In the present study, we evaluated the effect of wild-type p53 (wt-p53) expression on TNF sensitivity, by introducing wt-p53 into MCF7/Adr cells in which p53 was deleted, via a recombinant adenovirus encoding p53 (Ad-p53). Our results indicate that infection with Ad-p53 (50-100 viral particles per cell) resulted in pronounced cytotoxicity, whereas infection with 10 viral particles per cell, which was weakly toxic for the MCF7/Adr cells, sensitized these cells to TNF-induced cell death. Moreover, expression of wt-p53 in MCF7/Adr cells induced the production of reactive oxygen intermediates (ROIs) and caused glutathione (GSH) depletion, indicating disturbances in the cellular redox state. Additional treatment of cells with the anti-oxidant and glutathione (GSH) precursor N-acetylcysteine (NAC) resulted in inhibition of p53-induced ROIs production and in partial restoration of intracellular GSH levels, which was associated with the ability of NAC to inhibit p53-modulated TNF-induced cytotoxicity. Interestingly, Ad-p53 was able to inhibit TNF-induced MnSOD mRNA expression in MCF7/Adr cells, which might contribute to the sensitization of cells to the cytotoxic action of TNF. Taken together, our data strongly suggest that wt-p53 expression sensitizes TNF-resistant MCF7 cells with p53 deletion to TNF-induced cell death by a pathway that is dependent on ROIs production.
 ...
PMID:Adenovirus-mediated wild-type-p53-gene expression sensitizes TNF-resistant tumor cells to TNF-induced cytotoxicity by altering the cellular redox state. 1058 90

Retinoids modulate the growth and differentiation effects of TNF but the mechanism is not understood. In this study, we investigated the effect of all-trans-retinoic acid (ATRA) on the cell surface expression of TNF receptors and receptor-mediated signaling in various human lung cancer cell lines. ATRA treatment of cells that express wild-type p53 (A549 and H460), or null p53 (H1299), or mutant p53 (H596) increased the number of TNF receptors, as determined by the specific binding of 125I-labeled TNF to these cells, in a dose- and time-dependent manner. Treatment with 2 microm ATRA for 24 h at 37 degrees C produced the maximal increase. Scatchard analysis indicated that the increase induced by ATRA was due to an increase in receptor number and not to an increase in affinity. The upmodulation of TNF receptors was also confirmed by covalent receptor-ligand cross-linking studies. The increase in TNF receptors sensitized H596 cells to TNF-induced activation of NF-kappaB, AP-1 and apoptosis. A549 cells, however, were completely resistant to TNF-induced activation of NF-kappaB, AP-1 and apoptosis. Treatment of these cells with as little as 0.5 microM ATRA was effective in converting TNF-resistant cells to TNF-sensitive. Overall our results indicate that ATRA induces the TNF receptors in human lung cancer cells, which sensitizes them to TNF-induced signaling leading to activation of NF-kappaB, AP-1 and apoptosis.
 ...
PMID:All-trans-retinoic acid upregulates TNF receptors and potentiates TNF-induced activation of nuclear factors-kappaB, activated protein-1 and apoptosis in human lung cancer cells. 1081 2

This article reviews advances in the study of the molecular mechanisms for ultraviolet (UV)-induced keratinocyte apoptosis, with particular reference to the cytokines tumor necrosis factor-alpha (TNF-alpha) and Fas ligand (FasL). TNF-alpha and FasL induce their respective receptors and then activate caspase enzymes that are critically involved in the apoptotic process. This activation is further amplified by intracellular mitochondria-associated mechanisms. Using gene-targeted knockout mice lacking either the TNF-Rp55 or the TNF-Rp75, we have shown that TNF-alpha plays an important role in UV-induced keratinocyte apoptosis via TNF-Rp55. TNF-Rp55 shares homology with Fas and contains an intracellular death domain. UV seems to directly stimulate cross-linking of Fas, resulting in the engagement of the death machinery. Fas-associated death domain protein (FADD) acts as an adapter protein in both the TNF-Rp55 and Fas death-inducing cascades and is responsible for downstream signal transduction by recruiting caspases. Moreover, signaling of p53 contributes to the induction of apoptosis by regulating Bcl-2 family expression and increasing surface Fas expression. In addition to induction mechanisms of apoptosis, there are numerous inhibitory molecules that play a role in restricting the apoptotic pathway. Thus, the ultimate determination of whether or not a cell undergoes apoptosis after UV radiation is based on the balance between agonist and antagonist pathways.
 ...
PMID:Molecular mechanism of ultraviolet-induced keratinocyte apoptosis. 1084 Oct 72

Regulation of the homeostatic balance between cell proliferation and programmed cell death, apoptosis, is essential for development and maintenance of multicellular organisms. Apoptosis is a genetically and evolutionarily highly conserved process. Analysis of the molecular mechanisms of apoptosis has led to a better understanding of many human diseases. Notably in cancer, but also in infectious or autoimmune disease, a deficiency in apoptosis is one of the key events in pathophysiology. On the other hand, overefficient apoptosis, as observed in fulminant liver failure, may be equally harmful for the organism indicating that a tight regulation of the apoptotic machinery is essential for survival. The execution of apoptosis may be initiated by many different signals, either from within or outside the cell involving ligand-receptor interactions, as has been shown for Fas/Fas-ligand, TNF-alpha/TNF-receptor or TGF-beta/TGF-receptor, or potentially by more unspecific signals such as ceramide or DNA damage. During the modulation phase of apoptosis many different genes such as p53, c-myc or Bcl-2/Bax have been shown to able to shift the balance either to cell survival or cell death.
 ...
PMID:Apoptosis and the liver. 1093 67

Apoptosis is a prerequisite to model the developing nervous system. However, an increased rate of cell death in the adult nervous system underlies neurodegenerative disease and is a hallmark of multiple sclerosis (MS) Alzheimer's- (AD), Parkinson- (PD), or Huntington's disease (HD). Cell surface receptors (e.g., CD95/APO-1/Fas; TNF receptor) and their ligands (CD95-L; TNF) as well as evolutionarily conserved mechanisms involving proteases, mitochondrial factors (e.g. , Bcl-2-related proteins, reactive oxygen species, mitochondrial membrane potential, opening of the permeability transition pore) or p53 participate in the modulation and execution of cell death. Effectors comprise oxidative stress, inflammatory processes, calcium toxicity and survival factor deficiency. Therapeutic agents are being developed to interfere with these events, thus conferring the potential to be neuroprotective. In this context, drugs with anti-oxidative properties, e.g., flupirtine, N-acetylcysteine, idebenone, melatonin, but also novel dopamine agonists (ropinirole and pramipexole) have been shown to protect neuronal cells from apoptosis and thus have been suggested for treating neurodegenerative disorders like AD or PD. Other agents like non-steroidal anti-inflammatory drugs (NSAIDs) partly inhibit cyclooxygenase (COX) expression, as well as having a positive influence on the clinical expression of AD. Distinct cytokines, growth factors and related drug candidates, e.g., nerve growth factor (NGF), or members of the transforming growth factor-beta (TGF-beta ) superfamily, like growth and differentiation factor 5 (GDF-5), are shown to protect tyrosine hydroxylase or dopaminergic neurones from apoptosis. Furthermore, peptidergic cerebrolysin has been found to support the survival of neurones in vitro and in vivo. Treatment with protease inhibitors are suggested as potential targets to prevent DNA fragmentation in dopaminergic neurones of PD patients. Finally, CRIB (cellular replacement by immunoisolatory biocapsule) is an auspicious gene therapeutical approach for human NGF secretion, which has been shown to protect cholinergic neurones from cell death when implanted in the brain. This review summarises and evaluates novel aspects of anti-apoptotic concepts and pharmacological intervention including gene therapeutical approaches currently being proposed or utilised to treat neurodegenerative diseases.
 ...
PMID:Apoptosis modulators in the therapy of neurodegenerative diseases. 1106 Jul 7

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.
 ...
PMID:JunD protects cells from p53-dependent senescence and apoptosis. 1110 50

Advancement of genome analysis might give great impact to the treatment of inflammatory bowel diseases(IBD). IBD patients are treated by sulfadrugs, steroids and anti-immune drugs. For difficult cases, leukocytapheresis, beclomethasone dipropionate, anti-TNF therapy, anti-LTB4 therapy and other new methods are applied. Developing epoch-making drugs will be achieved by finding new molecular targets. Histologic identification of dysplasia is important in the surveillance of long-standing ulcerative colitis. The molecular diagnosis is required for the distinction of dysplasia from the regenerative inflammatory changes. P53 immunostaining have been proved useful. Various molecular targets will be taken into discussion as additional procedures. Recent genome analysis have revealed some genetic factors contribute to pathogenesis of IBD, which are HLA, IL4, MUC3, IBD1 locus, IBD2 locus and so on. More information about genes concerning IBD will be provided by analyzing dense SNP map using DNA tip. They will open the way to the tailored therapy.
 ...
PMID:[Post-genome challenges against inflammatory bowel diseases]. 1119 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>