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)

Mouse mortalin proteins, mot-1 and mot-2, differ by only two amino acid residues in their C-terminus. In previous studies we showed that they differ in their subcellular distributions and interactions with the tumor suppressor protein, p53. By using mot-1 deletion mutants and amino acid substitution constructs, we report here that inability of mot-1 to affect p53 activity in vivo is dependent on the presence of both of the unique mot-1 amino acids and all three of the predicted hsp70, EF hand, and leucine zipper motif regions. The two proteins and their single amino acid mutants showed different mobilities on SDS-polyacrylamide gel presenting an evidence for their different secondary structures. Taken together, the data suggest that each of the two differing amino acids between mot-1 and mot-2 is an important determinant of their secondary structures and in vivo activities.
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PMID:Transcriptional inactivation of p53 by deletions and single amino acid changes in mouse mot-1 protein. 1111 32

MKT-077, a cationic rhodacyanine dye analogue has been under preclinical cancer therapeutical trials because of its selective toxicity to cancer cells. Its cellular targets and mechanism of action remain poorly understood. Here we report that MKT-077 binds to an hsp70 family member, mortalin (mot-2), and abrogates its interactions with the tumor suppressor protein, p53. In cancer cells, but not in normal cells, MKT-077 induced release of wild-type p53 from cytoplasmically sequestered p53-mot-2 complexes and rescued its transcriptional activation function. Thus, MKT-077 may be particularly useful for therapy of cancers with wild-type p53.
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PMID:Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function. 1115 71

Approximately 50% of human tumours lack functional p53 suppressor protein. A promoter that is repressed by p53 in healthy cells could thus provide tumour-specific gene expression for a huge subset of tumours. In this report we describe a double recombinant adenovirus vector, 'Ad.p53R', encoding a therapeutic gene that is indirectly repressed by endogenous wild-type p53. Ad.p53R contains two independent expression cassettes; (1) the E. coli nitroreductase gene (NTR) driven by the human hsp70 promoter containing LacI binding sites (hsp70lacO-NTR) and (2) a p53-inducible lac repressor gene (tkGC3-lacI). In p53 null cells (Hep3B), Ad.p53R directed the same level of NTR expression as Ad.p53NR which lacks the tkGC3-lacI cassette. Moreover, injection of SW480 xenografts (mutated p53) with Ad.p53R resulted in a clear inhibition of growth in response to the prodrug CB1954. In cells retaining wt p53 (HepG2 and primary human endothelial cells), Ad.p53R expressed significantly less NTR (approximately 70%) than Ad.p53NR. Ad.p53R administered by i.v. injection also produced significantly less NTR than Ad.p53NR in normal tissues in vivo. Finally, adenovirus infection per se of cultured HepG2 cells at low MOI induced p53 stabilisation suggesting that adenovirus-mediated gene delivery may contribute to p53-based selectivity.
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PMID:Tumour-specific therapeutic adenovirus vectors: repression of transgene expression in healthy cells by endogenous p53. 1131 1

The present study was undertaken to determine the expression pattern of the hsp70 and the hsp27 genes in 106 cases of non-small cell lung carcinoma (NSCLC). We have shown that in the majority of cases (95/106) the HSP70 immunoreactivity was localized both in the cytoplasm and the nuclei. We also observed an enhanced nuclear immunoreaction for HSP70 in dysplastic lesions and in stage I tumors. In the case of the HSP27 we found a positive cytoplasmic immunostaining in 70% of cases, with the highest score in squamous cell carcinoma (SCC). We noted a positive correlation between the expression level of HSP27 and HSP70. There was a correlation between Ki-67 proliferation index and nuclear HSP70 staining, but not for HSP27. No association between the HSPs and the expression of pRb p16 and p21WAF1/CIP1 and p53 was found as studied previously. An interesting and statistically significant relationship was found between the expression of cyclin D1 and high intensity of HSP27 and HSP70 immunostaining. The relation of our results concerning the expression pattern of the HSP70 and HSP27 in NSCLC to those obtained by others for different types of primary tumors is discussed.
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PMID:Expression of heat shock proteins HSP70 and HSP27 in primary non-small cell lung carcinomas. An immunohistochemical study. 1139 34

Stabilization and overexpression are hallmarks of mutant p53 found in nearly 50% of human tumors. Mutations in the conformation-sensitive core domain of p53 often lead to association with molecular chaperones such as hsp70 and hsp90. Inhibition of hsp90 function accelerates mutant p53 degradation. We recently found that expression of p53 core domain mutants inhibits MDM2 degradation, suggesting that mutant p53 can modulate MDM2 functions. In this report, we show that mutant p53 mediates formation of MDM2-p53-hsp90 complexes. Release of MDM2 from the p53-hsp90 complex after DNA damage restores MDM2 but not p53 turnover, whereas dissociation of hsp90 by geldanamycin increases the degradation of both MDM2 and mutant p53. Mutant p53 degradation after hsp90 inhibition requires MDM2 expression. The interaction between MDM2 and hsp90 is disrupted by the 2A10 antibody, which recognizes a site on MDM2 important for binding to alternative reading frame (ARF). Expression of mutant p53 prevents MDM2 from binding ARF and accumulating in the nucleolus in an hsp90-dependent fashion. These results suggest that hsp90 recruited by mutant p53 conceals the ARF-binding site on MDM2 and inhibits its ubiquitin-protein isopeptide ligase function, resulting in the stabilization of both mutant p53 and MDM2.
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PMID:Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization. 1150 88

Heat shock protein hsp27 is a molecular chaperone and identification of hsp27-binding proteins might help to elucidate its functional role in keratinocyte biology. In the present investigation we used a human epidermal cell carcinoma cell line (A431) transfected with hsp27 (A431/16) to study interference between hsp27 protein and other proteins. Immunoprecipitation experiments with anti-hsp27 antibody revealed a multicomponent complex when analysed by silver staining. By immunoblotting analysis we could demonstrate that hsp27 associates with actin, the mutant form of p53, hsp70 and hsp90. Immunofluorescence analysis showed a co-localization between hsp27 and p53, hsp70 and hsp90. To control for the specificity of the observed interactions, immuno-precipitations with antibodies to actin, p53, hsp70 and hsp90 respectively, were performed. All of the tested proteins demonstrated a coimmunoprecipitation with hsp27. We conclude that hsp27, like the other heat shock proteins, is part of a complex system of molecular chaperones in epidermal keratinocytes.
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PMID:Characterization of proteins associated with heat shock protein hsp27 in the squamous cell carcinoma cell line A431. 1177 27

Increasing evidence provides support for oxidative stress to be closely linked to apoptosis. Reactive oxygen species (ROS) are thought to be involved in many forms of programmed cell death. Though heat shock is a universal phenomenon, BC-8, a macrophage-like cell line failed to mount a typical heat shock response. In the absence of heat shock proteins and functional p53, BC-8 cells undergo apoptosis through CD95 signaling. In the present study, we have investigated the role of ROS in the regulation of apoptosis in these cells. We show that cells transfected with hsp70 and functional p53 are resistant to heat-induced apoptosis through inhibition of CD95 expression and ROS induction. Furthermore, apoptosis in BC-8 cells resulted in two bursts of ROS generation, one correlated with heat stress and intracellular depletion of GSH and the other with Bax overexpression and cytochrome c release. Antioxidants could not protect these cells from heat-induced apoptosis and the death pathway seems to be dependent on initial signaling cascade subsequently altering the intracellular redox. Hence, our data suggest that ROS generation in BC-8 cells upon heat shock is facultative but not obligatory for apoptosis.
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PMID:A cross talk between cellular signalling and cellular redox state during heat-induced apoptosis in a rat histiocytoma. 1182 47

Tumor suppressor gene product p53 in its wild-type conformation, is an effector of apoptosis. A rat histiocytic tumor, AK-5 which has a rearranged and mutated p53 gene undergoes apoptosis upon heat shock through surface expression of CD95 receptor. DNA sequence analysis of p53 gene from tumor cells revealed a deletion of 'C' at nucleotide position 942 and an addition of 'A' at position 1055. Deletion of one nucleotide caused premature termination of p53 protein which resulted in shorter p53 protein with an altered sequence from amino acids 315 to 341. Altered p53 was unable to protect BC-8, a single cell clone of AK-5 cells from apoptosis upon heat shock. BC-8 cells transfected with a wild-type p53gene (3B4 cells) were resistant to heat induced apoptosis and did not show the expression CD95 death receptor. Inhibition of p53 expression by using antisense oligo induced apoptosis upon heat shock in 3B4 cells. Similarly, inhibition of CD95 expression by antisense oligo inhibited heat induced apoptosis in BC-8 cells. In addition, cell cycle regulatory molecules, cdc2 and cdk2 are differentially regulated in a non-cell cycle dependent manner in these tumor cells. These results, in view of lack of heat shock response in BC-8 cells suggest a complex interaction between p53, CD95 and hsp70 which determines the fate of the cell. In the absence of functional p53, CD95 appears to be an effector of apoptosis in BC-8 cells.
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PMID:Effect of C-terminal deletion of P53 on heat induced CD95 expression and apoptosis in a rat histiocytoma. 1203 86

Mortalin is a novel member of the hsp70 family of proteins that exhibits a different staining pattern in normal and immortal cells. It was also cloned as glucose regulated protein, GRP75 and peptidebinding protein, PBP74. It has been assigned multiple functions ranging from stress response, intracellular trafficking, antigen processing, control of cell proliferation, differentiation and tumorigenesis. The present article compiles and reviews information on multiple sites and functions of mortalin. In view of its upregulation in many tumors and transcriptional inactivation function of p53, its potential use in biotechnology and biomedicine is discussed.
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PMID:Mortalin: a potential candidate for biotechnology and biomedicine. 1237 Nov 45

The diffusion of extremely low-frequency (50 Hz) electromagnetic fields (ELF-EMF) in the human environment raises the question of the induction of biological effects of EMF on mammalian cells. We used the model of mouse pluripotent embryonic stem (ES) cells, which have the capacity to develop in vitro into cells of all lineages, to analyse non-thermal effects of ELF-EMF. Wild type (wt) and p53-deficient ES cells were exposed under controlled conditions to ELF-EMF signals simulating power-line (50 Hz) magnetic field (PL-MF) exposure. Different flux densities of 0.1 mT, 1.0 mT or 2.3 mT and intermittency schemes with various ON/OFF cycles were applied for 6 h or 48 h during the first stages of cell differentiation. Transcript levels of regulatory genes, such as egr-1, p21, c-jun, c-myc, hsp70 and bcl-2, were analysed by semi-quantitative RT-PCR immediately after exposure or after a recovery time of 18 h. Intermittent PL-MF exposure to 5 min ON/30 min OFF cycles at a flux density of 2.3 mT for 6 h resulted in a significant up-regulation of c-jun, p21 and egr-1 mRNA levels in p53-deficient, but not in wild-type cells. No significant effects were observed in both cell systems by PL-MF at lower flux densities, longer exposure time or after 18 h recovery time. Our data indicate that 5 min ON/30 min OFF intermittent PL-MF exposure is capable of evoking non-thermal responses in ES cells, dependent on the cellular p53 function. The nature of the biological responses triggered by PL-MF is discussed.
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PMID:Non-thermal effects of power-line magnetic fields (50 Hz) on gene expression levels of pluripotent embryonic stem cells-the role of tumour suppressor p53. 1470 19


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