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

The ovarian cancer cell lines A2780 (wild-type p53) and NIHOVCAR3 (mutated p53) showed, respectively, sensitivity and resistance towards several chemotherapy drugs. We hypothesized that the two cell lines differ in their ability to activate the intrinsic death pathway and have, therefore, dissected the lysosome-mitochondrion signalling pathway by pharmacological inhibition or genetic manipulation of key regulators and executioners. Biochemical and morphological confocal fluorescence studies showed that: (1) In A2780 cells bcl-2 is expressed at an undetectable level, whereas Bax is expressed at a rather high level; by contrast, bcl-2 is highly expressed and Bax is expressed at extremely low levels in NIHOVCAR3 cells; (2) Chemotherapy treatment reduced the expression of bcl-2 in NIHOVCAR3 cells, yet these cells resisted to drug toxicity; (3) Cathepsin D (CD), not cathepsin B or L, mediates the activation of the mitochondrial intrinsic death pathway in A2780 cells; (4) Lysosome leakage and cytosolic relocation of CD occurs in the chemosensitive A2780 cells, not in the chemoresistant NIHOVCAR3 cells; (5) Bax is essential for the permeabilization of both lysosomes and mitochondria in A2780 cells exposed to chemotherapy drugs; (6) CD activity is mandatory for the oligomerization of Bax on both mitochondrial and lysosomal membranes; (7) Bax activation did not occur in the resistant NIHOVCAR3 cells despite their high content in CD. The present data are consistent with a model in which on treatment with a cytotoxic drug the activation of a CD-Bax loop leads to the generalized permeabilization of lysosomes and eventually of mitochondria, thus reaching the point of no return, and culminates with the activation of the caspase cascade. Our data also imply that dysfunctional permeabilization of lysosomes contributes to the development of chemoresistance.
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PMID:Chemotherapy drug response in ovarian cancer cells strictly depends on a cathepsin D-Bax activation loop. 1865 25

We studied the effect of age and melatonin on cell death processes in brain aging. Senescence-accelerated prone mice 8 (SAMP8) and senescence-accelerated resistant mice (SAMR1) at 5 and 10 months of age were used as models of the study. Melatonin (10 mg/kg) or its vehicle (ethanol at 0.066%) was administered in the drinking water from 1 to 9 months of age. Neurodegeneration, previously shown in the aged brain of SAMP8 and SAMR1 at 10 months of age, may be due to a drop in age-related proteolytic activities (cathepsin D, calpains, and caspase-3). Likewise, lack of apoptotic and macroautophagic processes were found, without apparent modification by melatonin. However, the caspase-independent cell death, owing to high p53 and apoptosis-inducing factor (AIF) levels, might be an alternative pathway of cell death in the aged brain. The main effects of melatonin treatment were observed in the aged SAMR1 mice; in this strain we observed a marked increase in antioxidant activity (catalase and superoxide dismutase). Likewise, a key antioxidant role of apoptosis-related proteins, Bcl-2 and AIF, was suggested in the aged brain of SAM mice, which was clearly influenced by melatonin. Moreover, the age-related increase of lysosomal activity of cathepsin B and a lysosomal membrane-associated protein 2 supports the possibility of the maintenance of lysosomal viability in addition to age-related impairments of the proteolytic or macroautophagic activities. The effectiveness of melatonin against the oxidative stress-related impairments and apoptosis during the aging process is, once more, corroborated in this article.
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PMID:Melatonin alters cell death processes in response to age-related oxidative stress in the brain of senescence-accelerated mice. 1909 Sep 13

Recently, there has been an increased interest in unravelling the molecular mechanisms and cellular pathways controlling the differentiation and proliferation of human stem cell lines. Proteome analysis has proven to be an effective approach to comprehensive analysis of the regulatory network of differentiation. In the present study we applied 2-DE combined with capillary-LC-MS/MS analysis to profile differentially regulated proteins upon differentiation of dental follicle precursor cells (DFPCs). Out of 115 differentially regulated proteins, glutamine synthetase, lysosomal proteinase cathepsin B proteins, plastin 3 T-isoform, beta-actin, superoxide dismutases, and transgelin were found to be highly up-regulated, whereas cofilin-1, pro-alpha 1 collagen, destrin, prolyl 4-hydrolase and dihydrolipoamide dehydrogenase were found to be highly down-regulated. The group of up-regulated proteins is associated with actin-bundling and defence against oxidative cellular stress, whereas down-regulated proteins were associated with collagen biosynthesis. Bioinformatic analyses of the entire data set confirmed these findings that represent significant steps towards the understanding of DFPC differentiation. The bioinformatic analyses suggest that proteins associated with cell cycle progression and protein metabolism were down-regulated and proteins involved in catabolism, cell motility and biological quality were up-regulated. These results display the general physiological state of DFPCs before and after osteogenic differentiation. We also identified regulatory proteins, such as the transcription factors TP53 and Sp-1, associated with the differentiation process. Further studies will investigate the impact of identified regulatory proteins for cell proliferation and osteogenic differentiation in DFPCs.
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PMID:Proteomic analysis of osteogenic differentiation of dental follicle precursor cells. 1928 89

XIAP is an important antiapoptotic protein capable of conferring resistance to cancer cells. Embelin, the small molecular inhibitor of XIAP, possesses wide spectrum of biological activities with strong inhibition of nuclear factor kappa B and downstream antiapoptotic genes. However, the mechanism of its cell death induction is not known. Our studies using colon cancer cells lacking p53 and Bax suggest that both lysosomes and mitochondria are prominent targets of embelin-induced cell death. Embelin induced cell-cycle arrest in G(1) phase through p21, downstream of p53. In the absence of p21, the cells are sensitized to death in a Bax-dependent manner. The loss of mitochondrial membrane potential induced by embelin was independent of Bax and p53, but lysosomal integrity loss was strongly influenced by the presence of p53 but not by Bax. Lysosomal role was further substantiated by enhanced cathepsin B activity noticed in embelin-treated cells. p53-dependent lysosomal destabilization and cathepsin B activation contribute for increased sensitivity of p21-deficient cells to embelin with enhanced caspase 9 and caspase 3 activation. Cathepsin B inhibitor reduced cell death and cytochrome c release in embelin-treated cells indicating lysosomal pathway as the upstream of mitochondrial death signaling. Deficiency of cell-cycle arrest machinery renders cells more sensitive to embelin with enhanced lysosomal destabilization and caspase processing emphasizing its potential therapeutic importance to address clinical drug resistance.
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PMID:Lysosomal destabilization and cathepsin B contributes for cytochrome c release and caspase activation in embelin-induced apoptosis. 1994 16

N,N-bis-(8-hydroxyquinoline-5-yl methyl)-benzyl substituted amines (HQNBA) represent a new class of compounds showing anti-cancer activity. At the chemical level the compounds were shown to react preferentially with thiol radicals which may lead to unfolded cysteine containing proteins and subsequent ER-stress. At the molecular level, treatment of U87 cells with this class of derivatives induced an over-expression of stress genes, including P53 and numerous P53 target genes. By generating shRNA U87 cell clones impaired in P53 expression we found that P53 mediates neither proliferation arrest of treated U87 cells nor over-expression of potential P53 targets. Moreover, we discovered that a representative HQNBA derivative (JLK1486) induces strong but transient senescence in U87 cells in a P53-independent manner. We demonstrate that, in contrast to its effect on established glioblastoma cell lines, JLK1486 induces extensive death of primary glioblastoma cells. We provide evidence that both caspase 3, and 7 activation, and cathepsin B and D activities account for at least part of this cell death.
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PMID:Alternative responses of primary tumor cells and glioblastoma cell lines to N,N-bis-(8-hydroxyquinoline-5-yl methyl)-benzyl substituted amines: cell death versus P53-independent senescence. 2104 14

Meningiomas are the most commonly occurring intracranial tumors and account for approximately 15-20% of central nervous system tumors. Patients whose tumors recur after surgery and radiation therapy have limited therapeutic options. It has also been reported recently that radiation triggers DNA repair, cell survival and cell proliferation, and reduces apoptosis via the induction of cellular protective mechanisms. Earlier studies have reported that proteases such as uPA, uPAR and cathepsin B play important roles in tumor progression. In the present study, we attempted to determine the effectiveness of two bicistronic siRNA constructs pUC (uPAR/cathepsin B) and pU2 (uPA/uPAR) either alone or in combination with radiation, both in in vitro and in vivo models. Transfection of a plasmid vector expressing double-stranded RNA for uPA, uPAR and cathepsin B significantly induced the sub-G0-G1 cell population by the mitochondrial intrinsic apoptotic pathway. Results showed that pUC efficiently enhanced sub-G0-G1 phases compared to pU2 and was more effective. Interestingly, we observed that in IOMM-Lee cell lines, combined treatment of radiation with pUC and pU2 is more effective in comparison to SF-3061 and MN cell lines. We showed that apoptosis caused by these bicistronic constructs involves Bcl-2, Bcl-xL, p53 inactivation, cytochrome c release from mitochondria and caspase-9 activation, followed by the activation of caspase-3. We also determined that apoptosis caused by pUC and pU2 involves a mechanism which includes inactivation of p53 by its translocation from nucleus to cytoplasm as confirmed by immunofluorescence, which shows the oncogenic potential of p53 in meningiomas. However, the simultaneous RNAi-mediated targeting of uPAR and cathepsin B (pUC), in combination with irradiation, has greater potential application for the treatment of human meningioma in comparison to pU2 by decreasing p53 expression both in vitro and in vivo.
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PMID:Oncogenic role of p53 is suppressed by si-RNA bicistronic construct of uPA, uPAR and cathepsin-B in meningiomas both in vitro and in vivo. 2129 90

Mechanisms and pathways responsible for cytotoxicity of sulforaphane (SF) in colon cancer cells with deleted p53 were investigated during 48 h of exposure. SF showed dose-dependent cytotoxicity and proapoptotic activity in the present model. In addition, in HCT-116 p53KO cells SF induced DNA damage with the subsequent cellular response and signaling not including p53 and caspase-2 pathways. Conversely, in SF-treated cells JNK was activated which led to an early lysosomal membrane permeabilization, release of cathepsin B and D and activation of Bid by specific cleavage. Concomitantly, the expression of Bax increased in the presence of JNK-mediated Bcl-2 inhibition which was followed by mitochondrial release of cytochrome c and activation of apoptosis. These results suggest that SF may be useful as a chemopreventive agent in colon cancer with inactivated or lost p53.
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PMID:Sulforaphane induces cytotoxicity and lysosome- and mitochondria-dependent cell death in colon cancer cells with deleted p53. 2155 98

Lysosomal membrane labilizing agents (incl. proapoptotic proteins of Bcl-2 family, LAPF, p53), estimation of lysosomal membrane permeabilization in living cells, the new data on differential permeabilization of lysosomal membranes, membrane stabilizing factors (incl. Hsp70), relations between lysosomal membrane damage, and initiation of apoptosis were considered. Signal effect of lysosomal membrane permeabilization is caused preferentially by release of cathepsin B and D in cytosol. Subsequent numerous pathways of apoptogenic signalization include proteolytic attack/activation on signal cytosolic proteins, mitochondria, procaspases, cell nuclei. The mainstream of the cell damage is connected with activation pf proapoptotic Bid and Bax, leading to permeabilization of the outer mitochondrial membrane, release of cytochrome c into cytosol and activation of caspase cascade. Translocation of the lysosoma enzymes in cytosol is capable to induce both the caspase-dependent and caspase-independent paths of apoptosis.
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PMID:[Lysosomal membrane permeabilization as apoptogenic factor]. 2167 10

Lysosomal regulation is a poorly understood mechanism that is central to degradation and recycling processes. Here we report that LAMTOR1 (late endosomal/lysosomal adaptor, MAPK and mTOR activator 1) downregulation affects lysosomal activation, through mechanisms that are not solely due to mTORC1 inhibition. LAMTOR1 depletion strongly increases lysosomal structures that display a scattered intracellular positioning. Despite their altered positioning, those dispersed structures remain overall functional: (i) the trafficking and maturation of the lysosomal enzyme cathepsin B is not altered; (ii) the autophagic flux, ending up in the degradation of autophagic substrate inside lysosomes, is stimulated. Consequently, LAMTOR1-depleted cells face an aberrant lysosomal catabolism that produces excessive reactive oxygen species (ROS). ROS accumulation in turn triggers p53-dependent cell cycle arrest and apoptosis. Both mTORC1 activity and the stimulated autophagy are not necessary to this lysosomal cell death pathway. Thus, LAMTOR1 expression affects the tuning of lysosomal activation that can lead to p53-dependent apoptosis through excessive catabolism.
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PMID:LAMTOR1 depletion induces p53-dependent apoptosis via aberrant lysosomal activation. 2251 74

The development of hypoxic areas often takes place in solid tumors and leads cells to undergo adaptive signalization like autophagy. This process is responsible for misfolded or aggregated proteins and nonfunctional organelle recycling, allowing cells to maintain their energetic status. However, it could constitute a double-edged pathway leading to both survival and cell death. So, in response to stress such as hypoxia, autophagic and apoptotic cells are often mixed. To specifically study and characterize autophagic cells and the process, we needed to develop a method able to (1) isolate autophagic subpopulation and (2) respect apoptotic and autophagic status. Sedimentation field-flow fractionation (SdFFF) was first used to monitor physical parameter changes due to the hypoxia mimetic CoCl(2) in the p53 mutated SKNBE2(c) human neuroblastoma cell line. Second, we showed that "hyperlayer" elution is able to prepare autophagic enriched populations, fraction (F3), overexpressing autophagic markers (i.e., LC3-II accumulation and punctiform organization of autophagosomes as well as cathepsin B overactivity). Conversely, the first eluted fraction exhibited apoptotic markers (caspase-3 activity and Bax increased expression). For the first time, SdFFF was employed as an analytical tool in order to discriminate apoptotic and autophagic cells, thus providing an enriched autophagic fraction consecutively to a hypoxic stress.
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PMID:Autophagic subpopulation sorting by sedimentation field-flow fractionation. 2300 75


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