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)

Apoptosis in keratinocytes is required for epidermal turnover, stratum corneum formation, and removal of ultraviolet-damaged premalignant cells. Its role in melanocyte homeostasis and transformation, on the other hand, has not been defined, although apoptosis resistance is a commonly recognized feature of melanoma. We examined the expression of apoptosis regulators in melanocytes, keratinocytes, melanoma, and HaCat cells. Melanocytic cells expressed relatively high levels of Bcl-2, Bcl-X(L), Mcl-1, C-IAP-1, C-IAP-2, XIAP, Livin, and Apaf-1. The only apoptotic regulator that was differentially expressed in melanoma cells and not melanocytes was Survivin, whereas Bax was expressed in melanocytes but not in most melanoma lines. Keratinocytic cells, on the other hand, expressed high levels of FLIP and were relatively deficient in Bcl-2 family proteins. Levels of p53 were highest in HaCat cells and some of the melanoma lines, and barely detectable in melanocytes and keratinocytes. Next, susceptibility of these cells types to apoptosis induced by ultraviolet B, the tyrosine analog 4-tert-butylphenol, and cytotoxic drugs was examined. Melanocytes were relatively resistant to ultraviolet B, whereas keratinocytes were unresponsive to 4-tert-butylphenol. Melanocytes and keratinocytes were generally less susceptible than melanoma lines and HaCat cells to etoposide, cisplatin, and staurosporine. Induction of apoptosis in these cell types was generally associated with decreased levels of Mcl-1, XIAP, and Livin, and increased levels of p53, whereas levels of other apoptotic regulators were unaltered. These results provide insights into the potential roles of apoptosis in the function and transformation of epidermal melanocytes and keratinocytes.
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PMID:Apoptosis regulators and responses in human melanocytic and keratinocytic cells. 1253 97

Both the protein kinase C (alpha/beta) inhibitor Go6976 and expression of dominant-negative nuclear factor (NF)-kappaB inhibitor kinase mutants: (a) blocked the growth and caused regression of a mammary tumor insyngeneic mice; (b) inhibited epidermal growth factor (EGF)-induced activation, nuclear translocation, and DNA-binding activity of NF-kappaB; and (c) caused apoptosis of EGF-stimulated cultured mammary tumor cells. cDNA microarray analysis revealed that these treatments reversed the expression changes of a subset of genes altered by EGF treatment. These included: up-regulation of proapoptotic genes of the tumor necrosis factor (TNF) pathway, death-associated protein (DAP) kinase, p53, and p21/Waf1; and down-regulation of inhibitors of apoptosis: inhibitor of apoptosis(IAP)-1 and X-IAP, TNF receptor-associated factor (TRAF)-2, and factors OX40 and 4-1BB. These results and our previous studies suggest the practicality of a target-directed chemotherapy for EGF-responsive breast cancers, by blocking NF-kappaB activation and thereby reinstating apoptosis.
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PMID:Apoptosis caused by chemotherapeutic inhibition of nuclear factor-kappaB activation. 1254 76

The pyrimidine analogue Ara-C and the purine analogues fludarabine and cladribine (2-CdA) are essential compounds in the treatment of acute myeloid leukemia (AML). Inhibition of cell proliferation and induction of apoptosis are the major mechanisms of cytotoxic agents to cause tumor cell death. Therefore, we studied whether Ara-C in combination with the purine analogues exerts synergistic or antagonistic effects on cell proliferation, phosphatidylserine exposure and disruption of mitochondrial membrane potential (MMP) in the AML cell lines HL60 and HEL. Furthermore, effects of the combination of Ara-C with bendamustine, a new bifunctional agent with alkylating activity and a purine nucleus, was investigated. Assessment by combination index analysis showed that Ara-C combined with fludarabine or bendamustine exhibited additive to antagonistic effects on inhibition of cell proliferation, induction of apoptosis as well as on disruption of mitochondrial membrane potential, independent of a simultaneous or consecutive (purine analogues before Ara-C) incubation schedule. In contrast, the combination of Ara-C with 2-CdA exclusively yielded synergistic effects. While inducing IC50 levels of apoptosis neither the antagonistic nor the synergistic drug combinations caused a specific expression pattern of apoptosis-associated proteins such as the pro- or antiapoptotic Bcl-2 family members, executioner caspases, IAPs (inhibitor of apoptosis proteins), proapoptotic Par-4, PARP, or p53. In conclusion, we here demonstrate that the in vitro efficacy of drug combinations containing Ara-C and purine analogues depends on the purine analogue applied, whereas incubation schedules or escalating dosages do not contribute to the synergistic effects.
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PMID:In AML cell lines Ara-C combined with purine analogues is able to exert synergistic as well as antagonistic effects on proliferation, apoptosis and disruption of mitochondrial membrane potential. 1269 Nov 59

Ubiquitin is a ubiquitously expressed 76 amino acid protein that can be covalently attached to target proteins, leading to their ubiquitination. Many ubiquitinated proteins are degraded by the proteasome, a 2000 kDa ATP-dependent proteolytic complex. Numerous studies have demonstrated that the ubiquitination and proteasome system plays an important role in controlling the levels of various cellular proteins and therefore regulates basic cellular processes such as cell cycle progression, signal transduction, and cell transformation. Ubiquitination also directly affects the function and location of target proteins. Recent studies found that ubiquitination-mediated degradation and change in activity regulate many molecules of the cell death machinery, such as p53, caspases, and Bcl-2 family members. Ring finger-containing members of the IAP (inhibitor of apoptosis) family proteins themselves can function as ubiquitin protein ligases to ubiquitinate their target proteins or promote autoubiquitination. It has been demonstrated that degradation of the IAP proteins is required for apoptosis to occur in some systems, indicating apoptosis proceeds by activating death pathways as well as eliminating "roadblocks" through ubiquitination. These new findings also suggest that ubiquitination is one of the major mechanisms that regulate apoptotic cell death and could be a unique target for therapeutic intervention.
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PMID:Regulation of apoptosis: the ubiquitous way. 1272 36

Activation of glutamate receptors can trigger the death of neurons and some types of glial cells, particularly when the cells are coincidentally subjected to adverse conditions such as reduced levels of oxygen or glucose, increased levels of oxidative stress, exposure to toxins or other pathogenic agents, or a disease-causing genetic mutation. Such excitotoxic cell death involves excessive calcium influx and release from internal organelles, oxyradical production, and engagement of programmed cell death (apoptosis) cascades. Apoptotic proteins such as p53, Bax, and Par-4 induce mitochondrial membrane permeability changes resulting in the release of cytochrome c and the activation of proteases, such as caspase-3. Events occurring at several subcellular sites, including the plasma membrane, endoplasmic reticulum, mitochondria and nucleus play important roles in excitotoxicity. Excitotoxic cascades are initiated in postsynaptic dendrites and may either cause local degeneration or plasticity of those synapses, or may propagate the signals to the cell body resulting in cell death. Cells possess an array of antiexcitotoxic mechanisms including neurotrophic signaling pathways, intrinsic stress-response pathways, and survival proteins such as protein chaperones, calcium-binding proteins, and inhibitor of apoptosis proteins. Considerable evidence supports roles for excitotoxicity in acute disorders such as epileptic seizures, stroke and traumatic brain and spinal cord injury, as well as in chronic age-related disorders such as Alzheimer's, Parkinson's, and Huntington's disease and amyotrophic lateral sclerosis. A better understanding of the excitotoxic process is not only leading to the development of novel therapeutic approaches for neurodegenerative disorders, but also to unexpected insight into mechanisms of synaptic plasticity.
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PMID:Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. 1272 91

Resistance to Fas-mediated apoptosis (FMA) has been implicated in the pathogenesis of hematologic malignancies. Recently, a collaborative study showed that germline Fas mutations represent a genetic risk factor for the development of Hodgkin's and non-Hodgkin lymphoma. Here, we report that transformed B cell lines from familial lymphoma patients show a range of sensitivity to Fas-mediated apoptosis with lymphocytes from two patients with a marked resistance to Fas-, but not p53-mediated cell death. Fas resistance in these cells was associated with reduced recruitment of the initiator caspase 8 compared to cFlip, an inhibitor of apoptosis, to the death-inducing signaling complex (DISC). A decreased ratio of caspase 8 to cFlip in total cell extracts as well as in the DISC was associated with a profound disturbance of the Fas signaling cascade. We propose here that the relative reduction in caspase 8 to cFlip in the Fas DISC confers a survival advantage to lymphocytes and predisposes to the development of malignancy in some familial lymphoma patients.
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PMID:Differential recruitment of caspase 8 to cFlip confers sensitivity or resistance to Fas-mediated apoptosis in a subset of familial lymphoma patients. 1280 43

Survivin is a novel inhibitor of apoptosis commonly detected in tissues during fetal development and in cancer, but not usually in normal tissues. Expression of this protein may be of prognostic significance and therapeutically relevant in many cancers. We assessed survivin expression in ovarian carcinoma, correlating results with expression of other anti-apoptotic (bcl-2, bcl-x, mutant p53) and pro-apoptotic (bax) markers, with prognostic parameters, and prognosis. Paraffin-embedded sections of 49 ovarian carcinoma were immunostained for survivin, bcl-2, bcl-x, bax, and p53. Expression was evaluated in nuclei and cytoplasm, as intensity (0-3+), and percentage of positive cells was scored on a four-tiered system with <10% as negative. Frequency of survivin, bcl-2, bcl-x, bax, and p53 was 73.5%, 36.7%, 93.9%, 77.6%, and 60.4%, respectively. There was significant correlation between nuclear survivin expression and grade (P =.0014), histologic type (P =.0376), and mutant p53 (P =.0414). Survivin expression did not correlate with bcl-2, bcl-x, or bax expression, stage, or overall or disease-free survival. The majority (74%) of ovarian carcinoma show survivin expression, which correlates with poor prognostic parameters (high grade, histologic type, p53 mutation) but not with survival. Therapeutic targeting of survivin in ovarian carcinoma is a future possibility.
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PMID:Survivin expression in ovarian carcinoma: correlation with apoptotic markers and prognosis. 1496 60

The sunburn cell (SBC), with its pyknotic nucleus and eosinophilic cytoplasm, is characteristic of mammalian epidermis after exposure to UVC and UVB radiation or UVA radiation in the presence of psoralens. SBC may be regarded as an example of apoptosis: controlled individual cell death. Since the discovery of apoptosis over thirty years ago, there has been a considerable increase in the knowledge of mechanisms involved in this process. DNA damage has been shown to be a major determinant of SBC production both in a p53-dependent and -independent manner. Extranuclear events such as activation of membrane bound death receptors also contribute to SBC formation. The development of new technologies and techniques has resulted in a better understanding of the mechanisms and machinery involved in apoptosis, triggered by various stimuli and in different cell types. Of particular importance has been the elucidation of regulatory molecules such as caspases, inhibitor of apoptosis proteins (IAP) and the role of mitochondria as key to the process of apoptosis and consequent production of SBC. This review attempts to give an update on those mechanisms involved and the occurrence and relevance of SBC in mammalian skin are discussed.
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PMID:The sunburn cell revisited: an update on mechanistic aspects. 1285 4

Cells expressing the envelope glycoprotein complex (Env) encoded by the human immunodeficiency virus can fuse with cells expressing Env receptors (CD4 and CXCR4). The resulting syncytia undergo apoptosis. We developed a cytofluorometric assay for the quantitation of syncytium formation and syncytial apoptosis. Using this methodology, we show that caspase activation in syncytia is inhibited by pharmacological or genetic intervention on cyclin-dependent kinase-1, p53, and mitochondrial membrane permeabilization (MMP). Thus, transfection of fusing cells with the viral mitochondrial inhibitor of apoptosis encoded by cytomegalovirus, a specific inhibitor of MMP, prevented the mitochondrial cytochrome c release and abolished simultaneously the activation of caspase-3. Conversely, inhibition of caspases did not prevent MMP. These results indicate that Env-elicited syncytial apoptosis involves the intrinsic (mitochondrial) pathway.
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PMID:Mitochondrion-dependent caspase activation by the HIV-1 envelope. 1455 4

Viruses have evolved various strategies to prevent premature apoptosis of infected host cells. Some of the viral genes mediating antiapoptotic functions have been identified by their homology to cellular genes, but others are structurally unrelated to genes of known function. In this study, we used a random, unbiased approach to identify such genes in the murine cytomegalovirus genome. From a library of random transposon insertion mutants, a mutant virus that caused premature cell death was isolated. The transposon was inserted within open reading frame m41. An independently constructed m41 deletion mutant showed the same phenotype, whereas deletion mutants lacking the adjacent genes m40 and M42 did not. Apoptosis occurred in different cell types, could be blocked by caspase inhibitors, and did not require p53. Within the murine cytomegalovirus genome, m41, m40, and m39 form a small cluster of genes of unknown function. They are homologous to r41, r40, and r39 of rat cytomegalovirus, but lack sequence homology to UL41, UL40, and UL37 exon 1 (UL37x1) which are located at the corresponding positions of the human cytomegalovirus genome. Unlike UL37x1 of human cytomegalovirus, which encodes a mitochondrion-localized inhibitor of apoptosis that is essential for virus replication, m41 encodes a protein that localizes to the Golgi apparatus. The murine cytomegalovirus m41 product is the first example of a Golgi-localized protein that prevents premature apoptosis and thus extends the life span of infected cells.
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PMID:Murine cytomegalovirus m41 open reading frame encodes a Golgi-localized antiapoptotic protein. 1455 49


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