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)

ESPSearch is a computer program for rapidly identifying nucleic acid or amino acid sequences of any length within any source sequence from promoters to entire genomes to protein libraries. ESPSearch utilizes a user-constructed database to identify many sequences simultaneously, including target sequences with wildcards and mismatches and user-specified patterns of those recognized sequences. Here we use ESPSearch to identify a variety of possible binding sites for dimeric artificial transcription factors within several p53 recognition sites and the promoter of the BAX gene. Heterodimeric and homodimeric proteins are designed using human zinc fingers by identifying groups of zinc finger binding sites meeting particular pattern constraints. ESPSearch is also used to estimate the specificity of each artificial transcription factor by searching the entire genome. Next, the specificity of several possible small interfering RNA (siRNA) sequences is determined by searching both the whole genome and the library of known human mRNAs. Finally, ESPSearch identifies proteins containing different forms of the LXXLL motif used in nuclear receptor-coactivator interactions from the human proteome, making use of user-defined groups of amino acids. ESPSearch could also be applied to other tasks involving sequence and pattern recognition on small and large scales. ESPSearch is freely available at http://web.chemistry.gatech.edu/-doyle/espsearch/.
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PMID:ESPSearch: a program for finding exact sequences and patterns in DNA, RNA, or protein. 1567 92

p53, the tumor suppressor protein, functions as a dimer of dimers. However, how the tetramer binds to the DNA is still an open question. In the crystal structure, three copies of the p53 monomers (containing chains A, B, and C) were crystallized with the DNA-consensus element. Although the structure provides crucial data on the p53-DNA contacts, the active oligomeric state is unclear because the two dimeric (A-B and B-C) interfaces present in the crystal cannot both exist in the tetramer. Here, we address the question of which of these two dimeric interfaces may be more biologically relevant. We analyze the sequence and structural properties of the p53-p53 dimeric interfaces and carry out extensive molecular dynamics simulations of the crystal structures of the human and mouse p53 dimers. We find that the A-B interface residues are more conserved than those of the B-C. Molecular dynamics simulations show that the A-B interface can provide a stable DNA-binding motif in the dimeric state, unlike B-C. Our results indicate that the interface between chains A-B in the p53-DNA complex constitutes a better candidate for a stable biological interface, whereas the B-C interface is more likely to be due to crystal packing. Thus, they have significant implications toward our understanding of DNA binding by p53 as well as p53-mediated interactions with other proteins.
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PMID:Comparison of the protein-protein interfaces in the p53-DNA crystal structures: towards elucidation of the biological interface. 1573 97

S100B is a dimeric Ca(2+)-binding protein that undergoes a 90 +/- 3 degrees rotation of helix 3 in the typical EF-hand domain (EF2) upon the addition of calcium. The large reorientation of this helix is a prerequisite for the interaction between each subunit of S100B and target proteins such as the tumor suppressor protein, p53. In this study, Tb(3+) was used as a probe to examine how binding of a 22-residue peptide derived from the C-terminal regulatory domain of p53 affects the rate of Ca(2+) ion dissociation. In competition studies with Tb(3+), the dissociation rates of Ca(2+) (k(off)) from the EF2 domains of S100B in the absence and presence of the p53 peptide was determined to be 60 and 7 s(-)(1), respectively. These data are consistent with a previously reported result, which showed that that target peptide binding to S100B enhances its calcium-binding affinity [Rustandi et al. (1998) Biochemistry 37, 1951-1960]. The corresponding Ca(2+) association rate constants for S100B, k(on), for the EF2 domains in the absence and presence of the p53 peptide are 1.1 x 10(6) and 3.5 x 10(5) M(-)(1) s(-)(1), respectively. These two association rate constants are significantly below the diffusion control ( approximately 10(9) M(-)(1) s(-)(1)) and likely involve both Ca(2+) ion association and a Ca(2+)-dependent structural rearrangement, which is slightly different when the target peptide is present. EF-hand calcium-binding mutants of S100B were engineered at the -Z position (EF-hand 1, E31A; EF-hand 2, E72A; both EF-hands, E31A + E72A) and examined to further understand how specific residues contribute to calcium binding in S100B in the absence and presence of the p53 peptide.
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PMID:Calcium-binding properties of wild-type and EF-hand mutants of S100B in the presence and absence of a peptide derived from the C-terminal negative regulatory domain of p53. 1588 69

The p53 tumor suppressor protein binds to DNA as a dimer of dimers to regulate transcription of genes that mediate responses to cellular stress. We have prepared a cross-linked trapped p53 core domain dimer bound to decamer DNA and have determined its structure by x-ray crystallography to 2.3A resolution. The p53 core domain subunits bind nearly symmetrically to opposite faces of the DNA in a head-to-head fashion with a loophelix motif making sequence-specific DNA contacts and bending the DNA by about 20 degrees at the site of protein dimerization. Protein subunit interactions occur over the central DNA minor groove and involve residues from a zinc-binding region. Analysis of tumor derived p53 mutations reveals that the dimerization interface represents a third hot spot for mutation that also includes residues associated with DNA contact and protein stability. Residues associated with p53 dimer formation on DNA are poorly conserved in the p63 and p73 paralogs, possibly contributing to their functional differences. We have used the dimeric protein-DNA complex to model a dimer of p53 dimers bound to icosamer DNA that is consistent with solution bending data and suggests that p53 core domain dimer-dimer contacts are less frequently mutated in human cancer than intra-dimer contacts.
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PMID:Structure of the p53 core domain dimer bound to DNA. 1671 92

Resveratrol is a naturally occurring polyphenol, which causes apoptosis in cultured cancer cells. We describe a cell surface resveratrol receptor on the extracellular domain of hetero-dimeric alphaVbeta3 integrin in MCF-7 human breast cancer cells. This receptor is linked to induction by resveratrol of extracellular-regulated kinases 1 and 2 (ERK1/2)- and serine-15-p53-dependent phosphorylation leading to apoptosis. The integrin receptor is near the Arg-Gly-Asp (RGD) recognition site on the integrin; an integrin-binding RGD peptide inhibits induction by resveratrol of ERK1/2- and p53-dependent apoptosis. Antibody (Ab) to integrin alphaVbeta3, but not to alphaVbeta5, inhibits activation by resveratrol of ERK1/2 and p53 and consequent apoptosis in estrogen receptor-alpha (ERalpha) positive MCF-7, and ERalpha-negative MDA-MB231 cells. Resveratrol is displaced from the purified integrin by an RGD, but not RGE, peptide, and by alphaVbeta3 integrin-specific Ab. Resveratrol action is blocked by siRNAbeta3, but not by siRNAalphaV. [14C]-Resveratrol binds to commercially purified integrin alphaVbeta3 and to alphaVbeta3 prepared from MCF-7 cells; binding of [14C]-resveratrol to the beta3, but not to the alphaV monomer, is displaced by unlabeled resveratrol. In conclusion, binding of resveratrol to integrin alphaVbeta3, principally to the beta3 monomer, is essential for transduction of the stilbene signal into p53-dependent apoptosis of breast cancer cells.
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PMID:Integrin alphaVbeta3 contains a receptor site for resveratrol. 1679 May 23

Indenoisoquinolines are topoisomerase (Top) I inhibitors developed to overcome some of the limitations of camptothecins and expand their anticancer spectrum. Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}-propane bis(trifluoroacetate) (NSC 727357) is a novel dimeric indenoisoquinoline derivative with potent antiproliferative activity in the NCI-60 cell line panel, promising hollow fiber activity (score of 32) and activity against xenografts. Submicromolar concentrations of the bisindenoisoquinoline NSC 727357 induce Top1 cleavage complexes at specific sites in biochemical assays. At higher concentrations, inhibition of Top1 catalytic activity and DNA intercalation is observed. NSC 727357 also induces a limited number of Top2-DNA cleavage complexes. In contrast to the effect of other Top1 inhibitors, cells treated with the bisindenoisoquinoline NSC 727357 show an arrest of cell cycle progression in G(1) with no significant inhibition of DNA synthesis after a short exposure to the drug. Moreover, unlike camptothecin and the indenoisoquinoline MJ-III-65 (NSC 706744, 6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-5,11-diketo-2,3-dimethoxy-(methylenedioxy)-11H-indeno[1,2-c]isoquinoline hydrochloride), the cytotoxicity of bisindenoisoquinoline NSC 727357 is only partially dependent on Top1 and p53, indicating that this drug has additional targets besides Top1 and Top2.
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PMID:Bisindenoisoquinoline bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA intercalator and topoisomerase inhibitor with antitumor activity. 1679 38

The tetrameric state of p53, p63, and p73 has been considered one of the hallmarks of this protein family. While the DNA binding domain (DBD) is highly conserved among vertebrates and invertebrates, sequences C-terminal to the DBD are highly divergent. In particular, the oligomerization domain (OD) of the p53 forms of the model organisms Caenorhabditis elegans and Drosophila cannot be identified by sequence analysis. Here, we present the solution structures of their ODs and show that they both differ significantly from each other as well as from human p53. CEP-1 contains a composite domain of an OD and a sterile alpha motif (SAM) domain, and forms dimers instead of tetramers. The Dmp53 structure is characterized by an additional N-terminal beta-strand and a C-terminal helix. Truncation analysis in both domains reveals that the additional structural elements are necessary to stabilize the structure of the OD, suggesting a new function for the SAM domain. Furthermore, these structures show a potential path of evolution from an ancestral dimeric form over a tetrameric form, with additional stabilization elements, to the tetramerization domain of mammalian p53.
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PMID:Structural evolution of C-terminal domains in the p53 family. 1758 33

Nonmelanoma skin cancer (NMSC) is the most common type of human cancer. Solar ultraviolet radiation (UVR) is the main causative factor in the development of NMSC. UVR plays a variety of roles in the induction of skin cancers. It can serve as a complete carcinogen or as a promoter of carcinogenesis. The typical UV-induced DNA damage is the generation of dimeric photoproducts between adjacent pyrimidine bases. Tumor suppressor gene p53 is a common target of UVR-induced mutations. There is a proliferative advantage of p53 mutant keratinocytes over normal keratinocytes that eventuates in neoplastic transformation. While UVB causes considerable DNA damage in the skin, UVA has only recently been shown to induce pyrimidine dimers and oxygen and nitrogen reactive species which damage DNA, proteins and lipids. The immunosuppressive effect of UVR contributes to its carcinogenic activity. Finally, any one of these effects of UVR may contribute to the induction of skin cancers by other agents such as X-rays, viruses, or chemical carcinogens. The mechanism by which UVR leads to cutaneous malignant melanoma is less clear and it may be a cofactor rather than an initiator of this tumor. Primary prevention of UVR exposure is the most effective means of reducing UVR carcinogenesis. Systemic retinoids may influence the appearance of new tumors in patient populations at increased risk of developing NMSC such as xeroderma pigmentosum and organ transplant recipients, but their efficacy is hindered by their side effects.
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PMID:Ultraviolet radiation and cutaneous carcinogenesis. 1764 87

In addition to a well-defined transcriptional activity that is necessary for efficient apoptosis induction, the p53 tumor suppressor also has a direct apoptogenic role at the mitochondria. This direct role in cell death is mediated at least in part by interaction of p53 with BCL2 family members, including the pro-apoptotic protein BAK. Whereas it is currently accepted that the mitochondrial function of p53 contributes to its tumor suppressive role, the regulation of p53 function at this organelle is poorly understood. In this manuscript we examine the role of p53 oligomerization in the regulation of its pro-apoptotic function at the mitochondria, specifically in regard to its ability to induce BAK oligomerization. We find that deletion or mutation of p53's oligomerization domain markedly impairs the ability of this protein to oligomerize BAK. Along these lines, cross-linking studies indicate that the majority of p53 localized to mitochondria is in dimeric or higher-order oligomeric form. In support of the importance of the p53-BAK interaction in the localization of p53 to mitochondria, we find that mouse embryo fibroblasts from the BAK null mouse have greatly reduced mitochondrial p53 compared to wild type fibroblasts. These data indicate that pro-apoptotic BAK, unlike other BCL2 family members, may serve as a major receptor for p53 on the mitochondria.
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PMID:The tetramerization domain of p53 is required for efficient BAK oligomerization. 1789 45

The tumor suppressor protein p53 is considered the "Guardian of the Genome", crucial for cell cycle control and mutated in over 50% of human cancers. Following cellular stress, post-translational modifications such as phosphorylation and acetylation stabilise and activate p53 for cell cycle arrest, DNA repair, apoptosis or senescence. p53 protein functions as a tetramer and we have shown that loss of tetramerisation and changes at the N-terminus influence the recovery of wild type p53 'status'. To investigate the relationship between tetramerisation and post-translational modifications we examined a range of site-specific modifications in wild type and dimeric mutant (M340Q/L344R) murine p53 expressed in MEFs p53(-/-) and in wild type, monomeric (L344P) and dimeric (M340Q/L344R) human p53 expressed in HCT116 p53(-/-) cells. Using site-specific antibodies we demonstrate that in murine p53, S15 is phosphorylated in a tetramerisation-dependent manner. In contrast, human p53 S15 phosphorylation is not tetramerisation-dependent. Inability to form tetramers in human p53 proteins reduced site-specific N-terminal phosphorylation at S6, S9 and S46 and reduced C-terminal phosphorylation and acetylation at S315 and K382 respectively. In addition, p53 tetramerisation is required for efficient p21 and hdm2 transcription and protein expression and recruitment of p53 to specific promoter regions of p21 and hdm2.
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PMID:Influence of tetramerisation on site-specific post-translational modifications of p53: comparison of human and murine p53 tumor suppressor protein. 1876 32


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