Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 expression from a reporter construct driven by a cytomegalovirus (CMV) immediate early (IE) promoter is strongly inducible by UV in human fibroblasts. This response is induced at lower UV fluences in transcription-coupled repair (TCR)-deficient fibroblasts compared with normal fibroblasts and is absent in their simian virus 40-transformed counterparts. In this study we demonstrate that expression of human papilloma virus (HPV) E7 (but not of HPV E6) can attenuate UV-induced expression from the human CMV-IE-driven reporter construct in human fibroblasts. Furthermore, UV-induced expression from the reporter construct appears impaired in murine fibroblasts harboring inactivating mutations in the retinoblastoma (Rb) gene family members p107 and pRb but not in fibroblasts harboring such mutations in the p53 gene. Taken together, these data suggest that one or more members of the pRb family (but not p53) play an essential role in mediating UV-induced expression from the CMV-IE promoter. In this study we report normal UV-upregulation of reporter expression in xeroderma pigmentosum (XP) group E fibroblasts, consistent with normal TCR. Because XP-E cells deficient in the p48 subunit of the damaged DNA-binding protein are impaired in E2F-1-activated transcription, these results also suggest that the (pRb-regulated) transcription factor E2F-1 does not play an essential role in UV-enhanced expression from the CMV-IE promoter.
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PMID:Role for retinoblastoma protein family members in UV-enhanced expression from the human cytomegalovirus immediate early promoters. 1287 Aug 48

Infection by high-risk HPV (human papillomavirus) is supposed to be the primary cause of cervical cancer. The HPV E2 protein (E2) is a DNA-binding protein that regulates viral gene expression and is required for efficient viral replication. Overexpression of the E2 protein in cervical cancer cells can induce growth arrest and/or apoptotic cell death, suggesting that E2 might be useful in the treatment of this disease. In the present study, we show that VP22 (herpes simplex virus VP22 protein) can be used to deliver E2 to target cells. VP22-E2 fusion proteins induce apoptosis in transiently transfected HPV-transformed cervical carcinoma cell lines. However, VP22-E2 fusion proteins do not kill COS-7 cells, probably because these cells constitutively express the simian-virus-40 T antigen and this protein sequesters the tumour suppressor protein p53. When COS-7 cells producing VP22-E2 are seeded into cultures of HPV-transformed cells, VP22-E2 enters the non-producing cells and induces apoptosis. VP22-E2 proteins produced in bacterial cells can also enter cervical cancer cells and induce apoptosis in a dose-dependent manner. Our results suggest that local delivery of VP22-E2 fusion proteins could be used to treat cervical cancer and other HPV-associated diseases.
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PMID:Herpes simplex virus VP22-human papillomavirus E2 fusion proteins produced in mammalian or bacterial cells enter mammalian cells and induce apoptotic cell death. 1470 62

p53 is the most commonly mutated gene in human cancer. After activation by cellular stresses such as DNA damage or oncogene activation, p53, a sequence-specific DNA-binding protein, induces the expression of target genes which mediate tumor suppression. Two recently identified p53 homologues, p63 and p73, appear to function similarly to p53, that is, they both activate target gene expression and suppress cell growth when overexpressed; however, the p63 and p73 genes are rarely mutated in human cancer and do not adhere to Knudson's classical model of a tumor suppressor gene. Recently, exciting observations suggest nonoverlapping functions for the family members. Herein, we outline the recent literatures identifying and characterizing both the common and distinct target genes of the p53 family transcription factors in relation to their signaling pathways.
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PMID:The common and distinct target genes of the p53 family transcription factors. 1509 6

Antibodies to DNA are important markers of various autoimmune diseases and can be pathogenic; however, their generation is not understood. We previously reported that anti-DNA antibodies could be induced in mice by idiotypic immunization to PAb-421, an antibody to a DNA-binding domain of p53. We now report that two monoclonal antibodies of moderate affinity (K(D) asymptotically equal to 10(-7)), raised from PAb-421-immunized mice, specifically recognized both PAb-421 and DNA. These antibodies feature multiple arginine residues in the antigen-binding site, a unique characteristic of disease-associated anti-DNA antibodies; nevertheless, these anti-DNA antibodies show specific complementarity to PAb-421 by competing with p53 for PAb-421 binding and recognize defined oligonucleotides with a specificity similar to that of p53. To study the structural basis for the cross-recognition of PAb-421 and DNA by the anti-DNA antibodies, we constructed computer models (fine-tuned by protein-protein docking) of PAb-421 and one of the monoclonal anti-DNA antibodies. The modeled structures manifested structural complementarity. Most notably, the modeled structure of PAb-421 resembled the structure of DNA by the positions of negatively charged groups and aromatic side chains. Thus, a protein molecule may mimic the structure of DNA and the elusive generation of anti-DNA antibodies could be explained by idiotypic immunity to a DNA-binding protein, like p53.
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PMID:Monoclonal antibody to a DNA-binding domain of p53 mimics charge structure of DNA: anti-idiotypes to the anti-p53 antibody are anti-DNA. 1549 63

p53 tumor suppressor is a sequence-specific DNA-binding protein that controls the expression of many genes in response to diverse stress stimuli. p53 gene is often mutated in human cancer and in cancer cell lines. Several methods are available for identification of p53 mutations, including functional analysis of separated alleles in yeast (FASAY). FASAY distinguishes yeast colonies expressing functional p53 protein from colonies producing a dysfunctional p53 protein simply on the basis of color. We analyzed the p53 status of 26 human cell lines of different tissue origin using the functional assay in yeast. Wild-type p53 was found in six cell lines and various p53 aberrations in the remaining twenty. FASAY detected temperature-sensitive p53 mutations in breast cancer cell line, BT474, and leiomyosarcoma cell line, SK-LMS-1, and two independent p53 point mutations in SK-UT-1 and SK-LMS-1 leiomyosarcoma cell lines. In addition, the assay revealed that a recombination occurred between the two mutated p53 alleles producing a stable ratio of p53 wild-type alleles (11.7 or 2.7% respectively). In the case of acute myeloid leukemia cell line, ML-1, we detected both wild-type and heterozygous p53 status, depending on the source of the cell line. In Hs913T, HL60 and Saos-2 cell lines, FASAY failed to assess p53 status due to a large deletion/rearrangement of the p53 gene. In acute lymphoid leukemia HPB cell line, we disclosed unknown non-sense mutation in codon 124 of the p53 gene.
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PMID:Analysis of p53 status in human cell lines using a functional assay in yeast: detection of new non-sense p53 mutation in codon 124. 1614 49

Ligand activation of Notch leads to the release of Notch IC (the intracellular receptor domain), which translocates to the nucleus and interacts with the DNA-binding protein CSL to control expression of specific target genes. In addition to ligand-mediated activation, Notch signalling can be further modulated by interactions of Notch IC with a number of other proteins. MAML1 has previously been shown to act co-operatively with the histone acetyltransferase p300 in Notch IC-mediated transcription. In the present study we show that the N-terminal domain of MAML1 directly interacts with both p300 and histones, and the p300-MAML1 complex specifically acetylates histone H3 and H4 tails in chromatin. Furthermore, p300 acetylates MAML1 and evolutionarily conserved lysine residues in the MAML1 N-terminus are direct substrates for p300-mediated acetylation. The N-terminal domain of MAML1 contains a proline repeat motif (PXPAAPAP) that was previously shown to be present in p53 and important for the p300-p53 interaction. We show that the MAML1 proline repeat motif interacts with p300 and enhances the activity of the MAML1 N-terminus in vivo. These findings suggest that the N-terminal domain of MAML1 plays an important role in Notch-regulated transcription, by direct interactions with Notch, p300 and histones.
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PMID:A proline repeat domain in the Notch co-activator MAML1 is important for the p300-mediated acetylation of MAML1. 1730 Feb 19

The tumour suppressor gene ZAC/PLAGL1 is widely expressed in many human tissues during fetal development and throughout life. It encodes a DNA-binding protein which shares with p53 the ability to regulate apoptosis and cell cycle arrest concurrently. Owing to its anti-proliferative properties, down-regulation or loss of ZAC is believed to deregulate cell growth, and loss of expression has been observed in a number of different cancers. In addition, overexpression of ZAC during fetal development is believed to underlie the rare disorder transient neonatal diabetes mellitus (TNDM). Imprinted expression of ZAC has been demonstrated in many human and mouse tissues, although biallelic transcription has been noted in human peripheral blood leucocytes (PBL). We report here the identification of a second ZAC promoter, which is responsible for the observed biallelic expression. The promoter lies within a previously uncharacterized CpG island ~55 kb upstream of the imprinted CpG island. In PBL, the imprinted CpG island (P1) is differentially methylated and produces monoallelic transcripts, as in other tissues. However, biallelic transcripts predominate and are derived from the alternative CpG island (P2), which is unmethylated. Biallelic P2 expression was also found in adult pancreas, and ZAC expression from this promoter was identified at a low level in all adult human tissues tested. These findings show that regulation of ZAC expression is more complex than previously realized. The existence of the apparently independently-regulated P2 promoter has important implications for the study of ZAC dysregulation in cancer and TNDM.
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PMID:Tissue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of monoallelic and biallelic promoters. 1734 87

The RNA polymerase II transcription machinery acts as a molecular motor that traverses large parts of the genome on a regular basis. It has been suggested that the transcription machinery may play an important role in sensing DNA damage and activating DNA repair and stress response pathways when stalled at blocking lesions. We have collectively termed the activation of these different pathways as the transcription stress response. Recently, it was shown that the ATR kinase and the single-strand DNA-binding protein RPA mediate the phosphorylation of p53 following blockage of transcription elongation. This ATR-mediated phosphorylation occurs even when transcription elongation is blocked in the absence of DNA damage, suggesting that ATR and RPA senses the consequences of blocked transcription elongation rather than sensing DNA lesions directly. It is proposed that the transcription stress response activated by blockage of transcription may play an important role in safeguarding the genome from DNA damage and thus act to suppress tumorigenesis.
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PMID:The transcription stress response. 1770 65

Over 50% of all human cancers involve p53 mutations,which occur mostly in the sequence-specific DNA-binding central domain (p53c), yielding little/non-detectable af?nity to the DNA consensus site. Despite our current understanding of protein-DNA recognition,the mechanism(s) underlying the loss in protein-DNA binding afnity/ specificity upon single-point mutation are not well understood. Our goal is to identify the common factors governing the DNA-binding loss of p53c upon substitution of Arg 273 to His or Cys,which are abundant in human tumours. By computing the free energies of wild-type and mutant p53c binding to DNA and decomposing them into contributions from individual residues, the DNA-binding loss upon charge/noncharge -conserving mutation of Arg 273 was attributed not only to the loss of DNA phosphate contacts, but also to longer-range structural changes caused by the loss of the Asp 281 salt-bridge. The results herein and in previous works suggest that Asp 281 plays a critical role in the sequence-specific DNA-binding function of p53c by (i)orienting Arg 273 and Arg 280 in an optimal position to interact with the phosphate and base groups of the consensus DNA, respectively, and (ii) helping to maintain the proper DNA-binding protein conformation.
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PMID:Mechanism of DNA-binding loss upon single-point mutation in p53. 1791 25

The p53 tumor suppressor gene (TP53; OMIM: 191170) plays an important role in tumorigenesis in lung epithelial cells. TP53 encodes a sequence-specific DNA-binding protein that regulates transcription of several genes in response to DNA damage promoting cell cycle arrest, DNA repair or apoptosis. A mutation does not necessarily alter the protein function and since not all altered tumor protein p53 (TP53) conformations lead to the same biological properties, we studied Cys135Arg TP53 gene mutation in squamous cell type of non-small cell lung cancers (NSCLCs), by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and direct sequencing. Cys135Arg TP53 mutation, rare in databases (11/23544 in R11, IARC TP53 database), was detected. We chose p.C135R in order to examine DNA-TP53 interaction. A comparison with the wild-type after 1 nano-second molecular dynamic simulation analysis revealed a significant structural change (over 4A displacement) in the contact loop Lys-Ser-Val which lies upstream and next to the mutated site in the TP53, that sterically prevents its DNA-binding activity. Additionally, the mutation produced a change in the electrostatic potential surface of the protein in the same loop where the structural modification took place. To demonstrate the degree of loss of function, functional assays in yeast and bacteria with oligonucleotides for competitive electrophoretic mobility shift assays (EMSAs) were done proving that this mutation decreases TP53 ability to bind DNA of the TP53 response element from the human p21 gene. These results demonstrate that the amino acid change C135R in the human TP53 generates the loss of TP53 DNA-binding activity directly affecting its role as a transcription factor and suggests that this observation can explain part of the phenotype described in patients affected by this type of tumor.
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PMID:Loss of TP53-DNA interaction induced by p.C135R in lung cancer. 1791 75


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