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 gadd45 gene, a growth arrest and DNA damage (gadd)-induced gene, is transcriptionally activated by UV irradiation through two distinct pathways. One requires the sequence-specific binding of the p53 tumor suppressor protein to a responsive element within the third intron of the gadd45 gene, and the other is p53-independent activation of the gadd45 promoter region, although the UV-response element that mediates this has yet to be defined. To investigate the sequences involved in induction of gadd45 by UV irradiation in a p53-independent pathway, we performed mutation analyses of the human gadd45 promoter fused to the luciferase reporter gene in cell lines in which p53 was inactivated. We found that the UV-responsive element was involved in the Oct-1 binding site at -99 bp relative to the transcription start site. Electrophoretic mobility shift assays showed that Oct-1, a transcription factor, bound this element on the gadd45 gene, although the intensity and mobility pattern of the retarded bands were not altered by UV irradiation. These results suggest that the Oct-1 regulatory element might be one of the essential elements involved in the activation of the gadd45 promoter by UV irradiation in a p53-independent pathway.
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PMID:Involvement of the Oct-1 regulatory element of the gadd45 promoter in the p53-independent response to ultraviolet irradiation. 1122 50

Display on the surface of filamentous phages has been shown to be well suited for the enrichment of serum antibody-binding ligands. Here, we have taken the advantage of this technology to analyze the humoral immune response in patients with cancer. The cDNA repertoires from breast cancer cell lines T47D and MCF-7 were fused to the 3'-end of the filamentous phage M13 gene VI in all three reading frames. When the libraries were biopanned on rabbit polyclonal IgG against the human Bcl-x(L) protein, positive clones were selected, thus confirming the utility of the libraries. Using serum antibodies from patients with breast cancer, we specifically selected IgG-binding phage-encoded cDNA products. Sequence analysis of the selected clones identified important antigens including p53, centromere-F, int-2, pentraxin I, integrin beta5, cathepsin L2 and S3 ribosomal protein. The selected phage-displayed cDNA products were recognized by a significant number of breast cancer sera as compared to sera from normal individuals. Although the human pentraxin I mRNA was reported to be exclusively localized in the nervous system, we found it also expressed by breast cancer cell lines. Four out of 30 patients with breast cancer (13 %) showed reactivity with the recombinant pentraxin expressed in Escherichia coli, while no reactivity was found in normal sera. The obtained results demonstrate that phage display could be a valuable method for the identification of antigens recognized by the humoral immune system in patients with cancer.
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PMID:Profiling the immune response in patients with breast cancer by phage-displayed cDNA libraries. 1124 Dec 75

Mitochondrial localization of p53 has been observed in several cell systems, but an understanding of its organelle-based physiological activity remains incomplete. The purpose of the present study was to investigate the mitochondrial DNA genomic response to dominant-negative p53 mutant miniprotein (p53DD) fused to a mitochondrial import signal. Constructs were generated to express mitochondrial targeted enhanced green fluorescent protein (mEGFP) or dominant-negative mutant p53 miniprotein (m53DD) by in-frame fusion to the signal peptide sequence of murine Cox8l. Control cytosolic vectors (cEGFP, c53DD) had the signal sequence placed in antisense orientation. NIH 3T3 cells were transiently transfected with these vectors in various combinations. Mitochondrial 16S ribosomal RNA (16S rRNA) expression and fluorochrome staining with Mitotracker Red CMXRos (DeltaPsim) were decreased in cells expressing m53DD. Both alterations were specific for mitochondrial import competence (e.g., m53DD vs. c53DD) as well as the passenger protein (e.g., m53DD vs. mEGFP). The normal functional state of mitochondria was restored with PK11195, a specific ligand of the mitochondrial peripheral-type benzodiazepine receptor. Negative dominance of m53DD on 16S rRNA expression and CMXRos staining, and rescue of these parameters with PK11195, imply a direct positive effect of p53 on mitochondrial biogenesis and function.
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PMID:Direct influence of the p53 tumor suppressor on mitochondrial biogenesis and function. 1125 82

Experimental studies of complete mammalian genes and other genetic domains are impeded by the difficulty of introducing large DNA molecules into cells in culture. Previously we have shown that GST-Z2, a protein that contains three zinc fingers and a proline-rich multimerization domain from the polydactyl zinc finger protein RIP60 fused to glutathione S-transferase (GST), mediates DNA binding and looping in vitro. Atomic force microscopy showed that GST-Z2 is able to condense 130-150 kb bacterial artificial chromosomes (BACs) into protein-DNA complexes containing multiple DNA loops. Condensation of the DNA loops onto the Z2 protein-BAC DNA core complexes with cationic lipid resulted in particles that were readily transferred into multiple cell types in culture. Transfer of total genomic linear DNA containing amplified DHFR genes into DHFR(-) cells by GST-Z2 resulted in a 10-fold higher transformation rate than calcium phosphate co-precipitation. Chinese hamster ovarian cells transfected with a BAC containing the human TP53 gene locus expressed p53, showing native promoter elements are active after GST-Z2-mediated gene transfer. Because DNA condensation by GST-Z2 does not require the introduction of specific recognition sequences into the DNA substrate, condensation by the Z2 domain of RIP60 may be used in conjunction with a variety of other agents to provide a flexible and efficient non-viral platform for the delivery of large genes into mammalian cells.
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PMID:Condensation by DNA looping facilitates transfer of large DNA molecules into mammalian cells. 1132 83

A recently discovered potential tumor suppressor protein, Zac1, was previously shown to promote cell cycle arrest and apoptosis, and to act as a positive or negative transcriptional cofactor for nuclear receptors. Since these activities are common to Zac1 and p53, we tested for a functional interaction between these two proteins by investigating possible effects of Zac1 on the transcriptional activator function of p53. Zac1 specifically enhanced the activity of p53-responsive promoters in cells expressing wild type p53. The same promoters were not activated by Zac1 in cells lacking functional p53, but the Zac1 effect was restored by co-expression of p53. Zac1 bound to p53 and enhanced the activity of p53 or its N-terminal transcriptional activation domain fused to the DNA binding domain of Gal4. These results indicate that Zac1 served as a transcriptional coactivator for p53. The enhancement of p53 activity by Zac1 was much more dramatic in HeLa cells than in other cell lines tested. HeLa cells express human papillomavirus type 18 E6 protein which inactivates and causes the degradation of p53. Physical and functional interactions observed between Zac1 and E6 protein indicated that the dramatic activity of Zac1 in HeLa cells was due not only to Zac1's coactivator effect on p53, but also to the ability of Zac1 to reverse E6 inhibition of p53.
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PMID:Enhancement of p53-dependent gene activation by the transcriptional coactivator Zac1. 1136 Jan 97

In this study, we showed that nuclear ERK2 phosphorylates p53 at Thr55 in response to doxorubicin. p53 was found to physically interact with ERK2 as evidenced by Western blotting of ERK2 coimmunoprecipitated complex. The gene fragment encoded for N-terminal 68 amino acids was subcloned and fused with 6-His. Each serine or threonine site in this fragment, the possible phosphorylation site, was mutated to alanine. The recombinant proteins were used as substrates in ERK2 kinase assay. The results show that ERK2 phosphorylated p53 at Thr55. Further, electromobility shift assay showed that the phosphorylation of p53 by nuclear ERK2 was closely related to the transactivating activity of p53. These findings suggest that ERK2 may play a role in response to DNA damage via interaction with p53.
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PMID:Nuclear extracellular signal-regulated kinase 2 phosphorylates p53 at Thr55 in response to doxorubicin. 1140 76

The proto-oncogene Trks encode the high-affinity receptor tyrosine kinases for neurotrophins of a nerve growth factor (NGF) family. The Trk signals spatiotemporally regulate neural development and maintenance of neural network. However, Trk was originally cloned as an oncogene fused with the tropomyosin gene in the extracellular domain. Accumulating evidence has demonstrated that the rearranged Trk oncogene is often observed in non-neuronal neoplasms such as colon and papillary thyroid cancers, while the signals through the receptors encoded by the proto-oncogene Trks regulate growth, differentiation and apoptosis of the tumors with neuronal origin such as neuroblastoma and medulloblastoma. The intracellular Trk signaling pathway is also different depending on the Trk family receptors, cell types and the grade of transformation. Furthermore, developmentally programmed cell death of neuron, which is largely regulated by neurotrophin signaling, is at least in part controlled by tumor suppressors p53 and p73 as well as their antagonist DeltaNp73. Thus, the Trks and their downstream signaling function in both ontogenesis and oncogenesis. In this short review, the dynamic role of the Trk family receptors signaling in neural development, neurogenic tumors and other cancers will be discussed.
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PMID:Trk receptor tyrosine kinases: a bridge between cancer and neural development. 1143 Oct 98

The p53 protein, encoded by a tumor suppressor gene, mediates growth arrest or apoptosis in response to a variety of stresses. p53-dependent apoptosis, occurring in several sensitive tissues after radiation or chemotherapy, is partially responsible for the side effects of cancer treatment, making p53 a potential target for therapeutic suppression. p53 function can be suppressed by the ectopic expression of p53-derived peptides, isolated earlier using functional selection of genetic suppressor elements (GSEs) from a library of randomly fragmented p53 cDNA (Ossovskaya et al. [1996]. Proc. Natl. Acad. Sci. U.S.A. 93, 10309). The potent p53-suppressing GSE, GSE56, had been used to generate in an E. coli expression system a peptide with anti-p53 activity by fusion of the GSE-encoded sequence with penetratin, a 16-amino-acid-long peptide capable of efficient translocation through cell membranes. Fusion with penetratin does not affect the anti-p53 activity of retrovirus-transduced GSE56. The fused peptide was able to attenuate p53-mediated transactivation and apoptosis when added into culture media. Interestingly, GSE56-derived peptide with no penetratin also had accumulated in the cells and showed similar, though lower, anti-p53 activity. This study provides the rationale and methodological basis for efficient generation of biologically active peptides with therapeutic potential from GSEs isolated through functional selection.
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PMID:Generation of p53 suppressor peptide from the fragment of p53 protein. 1144 32

The p53 protein is the major tumor suppressor in mammals. The discovery of the p53 homologs p63 and p73 defined a family of p53 members with distinct roles in tumor suppression, differentiation, and development. Here, we describe the biochemical characterization of the core DNA-binding domain of a human isoform of p63, p63-delta, and particularly novel features in comparison with p53. In contrast to p53, the free p63 core domain did not show specific binding to p53 DNA consensus sites. However, glutathione S-transferase-fused and thus dimerized p63 and p53 core domains had similar affinity and specificity for the p53 consensus sites p21, gadd45, cyclin G, and bax. Furthermore, the fold of p63 core was remarkably stable compared with p53 as judged by differential scanning calorimetry (T(m) = 61 degrees C versus 44 degrees C for p53) and equilibrium unfolding ([urea](50%) = 5.2 m versus 3.1 m for p53). A homology model of p63 core highlights differences at a segment near the H1 helix hypothetically involved in the formation of the dimerization interface in p53, which might reduce cooperativity of p63 core DNA binding compared with p53. The model also shows differences in the electrostatic and hydrophobic potentials of the domains relevant to folding stability.
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PMID:High thermostability and lack of cooperative DNA binding distinguish the p63 core domain from the homologous tumor suppressor p53. 1147 76

Sensitivity to glucocorticoid (GC)-evoked apoptosis in lymphoid cell lines correlates closely with GC-mediated suppression of c-Myc expression. To establish a functional role for c-Myc in GC-mediated apoptosis, we have stably expressed MycER(TM), the human c-Myc protein fused to the modified ligand-binding domain of the murine estrogen receptor alpha, in GC-sensitive CEM-C7-14 cells. In CEM-C7-14 cells, MycER(TM) constitutively imparts c-Myc functions. Cells expressing MycER(TM) (C7-MycER(TM)) exhibited a marked reduction in cell death after 72 h in 100 nM dexamethasone (Dex), with 10-20-fold more viable cells when compared to the parental CEM-C7-14 clone. General GC responsiveness was not compromised, as evidenced by Dex-mediated suppression of endogenous c-Myc and cyclin D3, and induction of c-Jun and the glucocorticoid receptor. MycER(TM) also blunted Dex-mediated upregulation of p27(kipI) and suppression of the Myc target p53. In comparison to parental CEM-C7-14 cells, Dex-evoked DNA strand breaks were negligible and caspase activation was delayed, but the extent of G1 cell cycle arrest was similar in C7-MycER(TM) cells. Myc-ER(TM) did not result in permanent, complete resistance to GC however, and the GC-treated cells eventually died, indicative of redundant or interactive mechanisms in the GC-evoked lytic response of lymphoid cells. Our results emphasize the importance of c-Myc suppression in GC-evoked apoptosis of CEM-C7-14 cells.
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PMID:Constitutive expression of ectopic c-Myc delays glucocorticoid-evoked apoptosis of human leukemic CEM-C7 cells. 1149 86


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