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 transcriptional factor p53 is a regulatory protein which contributes to the preservation of tissue integrity by promoting either DNA repair or apoptosis. To establish the pathophysiological role of this protein in ischemia, we produced 1 h transient middle cerebral artery (MCA) occlusion in normal and in p53-deficient mice and investigated the resulting tissue damage by multiparametric imaging. Possible genetic influences on the angioarchitecture of the MCA territory and blood flow were examined by intravascular latex infusion and laser-Doppler flowmetry. Wild-type (p53(+/+)), heterozygous (p53(+/-)) and homozygous (p53(-/-)) mice deficient for the p53 gene did not differ in respect to angioarchitecture or the effect of vascular occlusion on blood flow and general physiological parameters. Twenty-four hours after 1 h MCA occlusion, mice revealed a gene dose-dependent decline in the size of metabolic disturbances (ATP depletion and inhibition of protein synthesis) and histological injury (Cresyl Violet staining). DNA fragmentations detected by terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL) did not differ in the three groups and were only present in ATP-depleted tissue. Our findings suggest that after transient focal brain ischemia p53 prevents rather than aggravates brain injury, and that this effect is brought about by mechanisms that are unrelated to the pro-apoptotic properties of this gene.
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PMID:Aggravation of brain injury after transient focal ischemia in p53-deficient mice. 1129 31

The relationship between apoptosis and chemosensitivity remains complex. We tested the chemosensitivity of 45 patients with advanced breast cancer (BC) ex vivo against anthracyclines (A: doxorubicin, epirubicin), taxanes (T: paclitaxel, docetaxel), cisplatin (DDP) and CMF and any correlation with the expression of p53, Bcl-2 and apoptosis. Viable cells were processed for ex vivo ATP Tumor Chemosensitivity Assay (ATP-TCA). Immunohistochemistry was performed in corresponding tumor samples. Apoptosis prior to chemotherapy was assayed using a TUNEL Test. Of 45 BC tested, 18 (40%) were p53+ and 37 (82%) showed high Bcl-2 expression. Apoptosis was detected in 29 (64.4%) specimens. The Ex vivo Response Rate (EVRR) for T was 75.6% in all cases. This was the highest rate among the 4 drugs tested followed by CMF (66.7%). For A and DDP the positive rates were lower (27.6% and 10.6%, respectively). A significant correlation (r = 0.589, p < or = 0.01) was found between tumors which were sensitive to A and DDP. There was no association between chemosensitivity and apoptosis. Moreover tests for p53 and Bcl-2 did not show a correlation to ex vivo chemosensitivity. Pretreatment apoptotic parameters are unlikely to predict the individual response of breast cancer to antineoplastic agents.
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PMID:Lack of correlation between P53 expression, BCL-2 expression, apoptosis and ex vivo chemosensitivity in advanced human breast cancer. 1132 70

Decreased mitochondrial membrane potential (DeltaPsi(M)) has been found in a variety of aging cell types from several mammalian species. The physiological significance and mechanisms of the decreased DeltaPsi(M) in aging are not well understood. This review considers the generation of DeltaPsi(M) and its role in ATP generation together with factors that modify DeltaPsi(M) with emphasis on mitochondrial membrane permeability, particularly the role of a multiprotein membrane megapore, the mitochondrial permeability transition pore complex (PTPC). Previous data showing decreased DeltaPsi(M) in aged cells is considered in relation to the methods available to estimate DeltaPsi(M). In the past the majority of studies used whole cell rhodamine 123 fluorescence to estimate DeltaPsi(M) in lymphocytes from mice or rats. Imaging of DeltaPsi(M) in living, in situ mitochondria using laser confocal scanning microscopy offers advantages over whole cell measurements or those from isolated mitochondria, particularly if several different potentiometric dyes are employed. Furthermore, high resolution imaging of the newer fixable potentiometric dyes allows immunocytochemistry for specific proteins and DeltaPsi(M) to be examined in the same cells or even the same mitochondria. We found that decreased DeltaPsi(M) in p53 overexpression-induced or naturally occurring senescence is associated with decreased responsiveness of the PTPC to agents that induce either its opening or closing. The decreased PTPC responsiveness seems to reflect, at least in part, decreased levels of a key PTPC protein, the adenine nucleotide translocase. We also consider the possible basis for decreased DeltaPsi(M) in fibroblasts from patients with Parkinson's disease, an age-related neurodegenerative disease. Finally, we speculate on the mechanisms and functional significance of decreased DeltaPsi(M) in aging.
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PMID:Mitochondrial membrane potential in aging cells. 1135 Nov 27

Topoisomerases constitute a family of highly conserved essential enzymes, which exist in all investigated living pro- and eukaryotic cells. They are indispensable for the control of DNA topology. Humans possess 4 types of topoisomerases, i. e. topoisomerase (topo) I, II, III and V. Topo I, a 100-kDa protein, is a member of the type-I enzyme group (type IB). Functionally, it is an ATP-independent DNA single-strand endonuclease and ligase that functions mainly during transcription but also during DNA replication. Topo II belongs to the type-II enzymes and is represented in humans by 2 highly homologous isoforms, alpha (170 kDa) and beta (180 kDa). Contrary to topo I, the 2 topo II isoforms are ATP-dependent double-strand endonucleases and ligases. Topo I and the beta-form of topo II are expressed in a proliferation-independent manner, whereas topo IIalpha is cell-cycle-regulated. Because of the crucial role of topoisomerases for the maintenance and replication of DNA during proliferation, cells become highly vulnerable when these functions are lost. Consequently, a wide range of drugs with cytostatic effects are topo inhibitors. Topo I inhibitors in clinical use belong to the camptothecin family, e. g. topotecan and irinotecan. Topo IIalpha inhibitors are constituents of most chemotherapeutic protocols and form a large heterogeneous group. It includes clinically used compounds such as the podophyllotoxin analogues etoposide and teniposide, the anthracyclines daunorubicin, doxorubicin and idarubicin, the anthracenedione mitoxantrone and amsacrine. Recently, substances with dual specificity that inhibit both topo I and topo IIalpha have been found. The clinical relevance of these new compounds remains to be established. Specific inhibitors of topo IIbeta have not been described yet. The majority of topo inhibitors interfere with the religation step in the normal action of the enzymes, which leads to a stabilisation of the so-called cleavable complex. This results in DNA single-strand breaks in the case of topo I or double-strand breaks in the case of topo II. DNA single-strand breaks due to topo I inhibition are converted into double-strand breaks in the course of DNA replication. Such topo-mediated DNA strand breaks likely induce repair or apoptosis mechanisms via p53 and/or p21(WAF1/Clip1). As a consequence, while topoisomerases are required for proliferation, proliferation is also essential for efficacious topo inhibition. The cell-cycle-dependent expression of topo IIwas also successfully used for prognostic evaluations of survival in patients with cancer. Copyright 2000 S. Karger GmbH, Freiburg
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PMID:Human DNA-Topoisomerases - Diagnostic and Therapeutic Implications for Cancer. 1144 Dec 36

The evolution of brain injury was examined in mice subjected to focal cerebral ischemia as induced by 30 min of intraluminar thread occlusion of the middle cerebral artery, followed by 3 h to 3 days of reperfusion. Metabolic dysfunctions were studied by 3H-leucine autoradiography for the measurement of cerebral protein synthesis and by regional ATP bioluminescent imaging. Metabolic changes were compared with responses of the genes c-fos, c-jun, heat-shock protein gene (hsp)72, p53-activated gene (pag)608 and caspase-3, which were investigated by in situ hybridization histochemistry and immunocytochemistry, and correlated with the degree of DNA fragmentation, as assessed by the terminal TdT-mediated dUTP-biotin nick end labeling method. Intraluminar thread occlusion led to a reproducible reduction of cerebral laser Doppler flow to 20-30% of control. Thread withdrawal was followed by a short-lasting post-ischemic hyperperfusion to approximately 120%. In non-ischemic control animals, fractional protein synthesis values of 0.81+/-0.26 and 0.94+/-0.23 were obtained. Thread occlusion resulted in a suppression of protein synthesis throughout the territory of the middle cerebral artery after 3 h of reperfusion (0.04+/-0.08 in caudate-putamen and 0.14+/-0.19 in somatosensory cortex, P<0.05). Protein synthesis partly recovered in the cortex after 24 h and 3 days (0.71+/-0.40 and 0.63+/-0.26, respectively), but remained suppressed in the caudate-putamen (0.14+/-0.22 and 0.28+/-0.28). Regional ATP levels did not show any major disturbances at the reperfusion times examined. Thread occlusion resulted in a transient increase of c-fos mRNA levels in ischemic and non-ischemic parts of the cortex and caudate-putamen at 3 h after ischemia, which suggests that spreading depressions were elicited in the tissue. At the same time, c-jun and hsp72 mRNAs were elevated only in ischemic brain areas showing inhibition of protein synthesis. C-fos and c-jun responses completely disappeared within 24 h of reperfusion. Hsp72 mRNA levels remained elevated in the cortex after 24 h, but decreased to basal values in the caudate-putamen. Twenty-four hours after reperfusion, pag608 and caspase-3 mRNA levels increased in the caudate-putamen, where protein synthesis rates were still reduced, and remained elevated even after 3 days. However, pag608 and caspase-3 mRNA levels did not increase in the cortex, where protein synthesis recovered. After 24 h and 3 days, functionally active p20 fragment of caspase-3 was detected in the caudate-putamen, closely associated with the appearance of DNA fragmented cells. Neither activated caspase-3 nor DNA fragmentation were noticed in the cortex.In summary, the suppression of protein synthesis is reversible in the ischemia-resistant cortex following 30 min of thread occlusion in mice, but persists in the vulnerable caudate-putamen. In the caudate-putamen, apoptotic programs are induced, closely in parallel with the manifestation of delayed cell death. Thus, the recovery of protein synthesis may be a major factor influencing tissue survival after transient focal ischemia.
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PMID:Relationship between metabolic dysfunctions, gene responses and delayed cell death after mild focal cerebral ischemia in mice. 1145 82

Using highly purified proteins, we have identified intermediate reactions that lead to the assembly of molecular chaperone complexes with wild-type or mutant p53R175H protein. Hsp90 possesses higher affinity for wild-type p53 than for the conformational mutant p53R175H. The presence of Hsp90 in a complex with wild-type p53 inhibits the binding of Hsp40 and Hsc70 to p53, consequently preventing the formation of wild-type p53-multiple chaperone complexes. The conformational mutant p53R175H can form a stable heterocomplex with Hsp90 only in the presence of Hsc70, Hsp40, Hop and ATP. The anti-apoptotic factor Bag-1 can dissociate Hsp90 from a pre- assembled complex wild-type p53 protein, but it cannot dissociate a pre-assembled p53R175H-Hsp40- Hsc70-Hop-Hsp90 heterocomplex. The results presented here provide possible molecular mechanisms that can help to explain the observed in vivo role of molecular chaperones in the stabilization and cellular localization of wild-type and mutant p53 protein.
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PMID:Co-chaperones Bag-1, Hop and Hsp40 regulate Hsc70 and Hsp90 interactions with wild-type or mutant p53. 1170 1

The present study aims at verifying whether aponecrosis, a novel type of cell demise sharing the features of both apoptosis and necrosis previously identified in in vitro experiments, could represent a natural phenomenon that also occurs in vivo. The pathways of cell death were analyzed morphologically in MCF-7 breast cancer cell tumors implanted into nude mice. These tumors grew as encapsulated masses devoid of blood vessels, thus allowing for the creation of a gradient of oxygen and nutrients from the periphery inwards. Expression of wild-type p53 and DNA fragmentation were investigated as apoptotic markers. Further experiments were carried out on MCF-7 cells cultured in vitro in the presence and absence of oxygen and nutrients. In these cultures, the intracellular ATP levels were measured and related to the types of cell death recognized morphologically. Apoptotic cells were observed in the outer portion of the MCF-7 cell tumors close to blood vessels. In the inner portion of the tumors which lacks blood supply, several cells simultaneously showed signs of both apoptosis and necrosis, being identifiable as aponecrotic cells. Similarly, aponecrotic cells were also observed in the starved cultures, in concomitance with intracellular ATP depletion. These findings suggest that MCF-7 cells may accomplish the apoptotic process only when sufficient oxygen and energy supply are available. As the energy level decreases, aponecrosis may ensue as the result of an incomplete execution of the apoptotic program.
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PMID:Energy-dependent types of cell death in MCF-7 breast cancer cell tumors implanted into nude mice. 1173 99

The vaccinia-related kinase 1 (VRK1) protein is a nuclear Ser-Thr kinase that phosphorylates p53 in Thr18. We have determined the enzyme properties regarding its different substrates. VRK1 has a high affinity for ATP (K(m) 50 microM) and is thus saturated by the intracellular concentration of ATP in vivo. VRK1 uses preferentially magnesium, but is also functional with manganese and zinc. The VRK1 protein is autophosphorylated in multiple residues without effect on its activity. One autophosphorylated residue, T355, is within the VRK1 regulatory carboxy terminus. The kinase phosphorylates p53 with a K(m) of 1 microM and is well suited to respond to the variations of intracellular p53 concentration, which fluctuates as a response to different types of cellular stress.
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PMID:Kinetic properties of p53 phosphorylation by the human vaccinia-related kinase 1. 1188 97

The SWI/SNF complex is required for the transcription of several genes and has been shown to alter nucleosome structure in an ATP-dependent manner. The tumor suppressor protein p53 displays growth and transformation suppression functions that are frequently lost in mutant p53 proteins detected in various cancers. Using genetic and biochemical approaches, we show that several subunits of the human SWI/SNF complex bind to the tumor suppressor protein p53 in vivo and in vitro. The transactivation function of p53 is stimulated by overexpression of hSNF5 and BRG-1 and dominant forms of hSNF5 and BRG-1 repress p53-dependent transcription. Chromatin immunoprecipitation assay shows that hSNF5 and BRG-1 are recruited to a p53-dependent promoter in vivo. Overexpression of dominant negative forms of either hSNF5 or BRG-1 inhibited p53-mediated cell growth suppression and apoptosis. Molecular connection between p53 and the SWI/SNF complex implicates that (i) the SWI/SNF complex is necessary for p53-driven transcriptional activation, and (ii) the SWI/SNF complex plays an important role in p53-mediated cell cycle control.
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PMID:SWI/SNF complex interacts with tumor suppressor p53 and is necessary for the activation of p53-mediated transcription. 1195 Aug 34

Raising osmolality to 700 mosmol/kgH(2)O by the addition of NaCl rapidly kills most murine inner renal medullary collecting duct cells (mIMCD3), but they survive at 500 mosmol/kgH(2)O. At 300 and 500 mosmol/kgH(2)O, NADH autofluorescence is present in a mitochondria-associated, punctate perinuclear pattern. Within 45 s to 30 min at 700 mosmol/kgH(2)O, the autofluorescence spreads diffusely throughout the cell. This correlates with mitochondrial membrane depolarization, measured as decreased tetramethylrhodamine methyl ester perchlorate (TMRM) fluorescence. Mitochondrial dysfunction should increase the cellular ADP/ATP ratio. In agreement, this ratio increases within 1-6 h. Mitochondrial morphology (transmission electron microscopy) is unaffected, but nuclear hypercondensation becomes evident. Progressive apoptosis occurs beginning 1 h after osmolality is raised to 700, but not to 500, mosmol/kgH(2)O. General caspase activity and caspase-9 activity increase only after 6 h at 700 mosmol/kgH(2)O. The mitochondrial Bcl-2/Bax ratio decreases within 1-3 h, but no cytochrome c release is evident. The mitochondria contain little p53 at any osmolality. Adding urea to 700 mosmol/kgH(2)O does not change NADH or TMRM fluorescence. We conclude that extreme acute hypertonicity causes a mitochondrial dysfunction involved in the initiation of apoptosis.
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PMID:Mitochondrial dysfunction is an early event in high-NaCl-induced apoptosis of mIMCD3 cells. 1199 14


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