Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus, type 1-encoded transactivator protein Tat is known to be a substrate of and to interact with several nuclear histone acetyltransferases (HATs). Here we show that Tat is a general inhibitor of histone acetylation by cellular HATs and that for at least one of them, the CREB-binding protein (CBP), it induces a substrate selectivity. Indeed, in the presence of Tat, the acetylation of histones by CBP was severely inhibited, while that of p53 and MyoD remained unaffected. The C-terminal domain of Tat, dispensable for the activation of viral transcription, was found to be necessary and sufficient to interfere with histone acetylation. These results demonstrate that Tat is able to selectively modulate cellular protein acetylation by nuclear HATs and therefore to take over this specific signaling system in cells.
 ...
PMID:Tat-controlled protein acetylation. 1215 97

Members of the evolutionarily conserved silent information regulator 2 (Sir2) protein family are nicotinamide adenine dinucleotide (NAD(+))-dependent histone deacetylases. In yeast, the founding Sir2 protein is known to function in transcriptional silencing processes through the deacetylation of histones H3 and H4, thus setting up a repressive chromatin structure. Yeast and Caenorhabditis elegans Sir2 are also involved in regulating the life span of these organisms. Until recently, the function of mammalian Sir2 family members was completely unknown. However, several recent studies have now determined a remarkable function for the human SIRT1 protein, which is the closest human homolog of yeast Sir2. SIRT1 specifically associates with the p53 tumor suppressor protein and deacetylates it, resulting in negative regulation of p53-mediated transcriptional activation. Importantly, p53 deacetylation by SIRT1 also prevents cellular senescence and apoptosis induced by DNA damage and stress.
 ...
PMID:Human Sir2 and the 'silencing' of p53 activity. 1222 Aug 51

Mutation of the p53 tumor suppressor gene is recognized to be a key event in the development of the highly aggressive behavior of undifferentiated or anaplastic thyroid carcinomas. Attempts to treat these carcinomas with p53 gene therapy have, however, been largely unsuccessful. Since epigenetic changes such as histone deacetylation are associated with loss of thyroid differentiation, we have evaluated the potential of combining p53 gene therapy with exposure to the histone deacetylase inhibitor (HDAC-1), depsipeptide. We used two carcinoma cell lines: FRO cells that express very low levels of p53 and WRO cells producing a dominant negative p53. A p53 response element luciferase assay showed that stimulation of p53 transcriptional activity by the combined treatment with the HDAC-1 and p53 was 10 to 100 times greater than with p53 alone. Western blot analysis demonstrated that the HDAC-1 increased the expression of acetylated histones, as well as of p21(cip1/waf1), but did not affect levels of total histone and endogenous p53. The combined treatment was much more effective than either treatment alone in inhibiting the growth of both cell lines, and flow cytometric analysis suggested that this was due to an increase in the sub-G1 apoptotic population. Our findings indicate that HDAC-1 enhances apoptotic killing by p53 transfer, and suggest that this combination strategy may be useful in treating undifferentiated thyroid carcinomas.
 ...
PMID:A histone deacetylase inhibitor enhances killing of undifferentiated thyroid carcinoma cells by p53 gene therapy. 1236 80

Histone acetyltransferases (HATs) use acetyl CoA to acetylate target lysine residues within histones and other transcription factors, such as the p53 tumor suppressor, to promote gene activation. HAT enzymes fall into subfamilies with divergence in sequence and substrate preference. Several HAT proteins have been implicated in human cancer. We have previously reported on the preparation of peptide-CoA conjugate inhibitors with distinct specificities for the p300/CBP [cAMP response element binding protein (CREB)-binding protein] or GCN5 HAT subfamilies. Here we report on the crystal structure of the GCN5 HAT bound to a peptide-CoA conjugate containing CoA covalently attached through an isopropionyl linker to Lys-14 of a 20-aa N-terminal fragment of histone H3. Surprisingly, the structure reveals that the H3 portion of the inhibitor is bound outside of the binding site for the histone substrate and that only five of the 20 aa residues of the inhibitor are ordered. Rearrangements within the C-terminal region of the GCN5 protein appear to mediate this peptide displacement. Mutational and enzymatic data support the hypothesis that the observed structure corresponds to a late catalytic intermediate. The structure also provides a structural scaffold for the design of HAT-specific inhibitors that may have therapeutic applications for the treatment of HAT-mediated cancers.
 ...
PMID:Structure of the GCN5 histone acetyltransferase bound to a bisubstrate inhibitor. 1239 Dec 96

The heterotrimeric transcription factor NF-Y recognizes with high specificity and affinity the CCAAT regulatory element that is widely represented in promoters and enhancer regions. The CCAAT box acts in concert with neighboring elements, and its bending by NF-Y is thought to be a major mechanism required for transcription activation. We have solved the structure of the NF-YC/NF-YB subcomplex of NF-Y, which shows that the core domains of both proteins interact through histone fold motifs. This histone-like pair is closely related to the H2A/H2B and NC2alpha/NC2beta families, with features that are both common to this class of proteins and unique to NF-Y. The structure together with the modeling of the nonspecific interaction of NF-YC/NF-YB with DNA and the full NF-Y/CCAAT box complex highlight important structural features that account for different and possibly similar biological functions of the transcriptional regulators NF-Y and NC2. In particular, it emphasizes the role of the newly described alphaC helix of NF-YC, which is both important for NF-Y trimerization and a target for regulatory proteins, such as MYC and p53.
 ...
PMID:The NF-YB/NF-YC structure gives insight into DNA binding and transcription regulation by CCAAT factor NF-Y. 1240 88

We investigated the cell cycle and apoptotic response to irradiation in 4 human ovarian carcinoma cell lines, i.e., PA-1, Caov-3, SK-OV-3, and ES-2. Cell lines were also analysed for their p53 and Bax expression to address the relationship with cell cycle and apoptotic response. Apoptosis was examined by flow cytometric measurement of annexin V binding and by determination of cytoplasmic histone-associated DNA fragments with a photometric enzyme immunoassay. Cell cycle analyses were performed on the basis of flow cytometry. p53 and Bax protein expression was examined by immunocytochemistry in untreated cells and after irradiation. p53 cDNA sequencing and a functional yeast-based assay (FASAY) were performed to determine the p53 mutational status. All cell lines exhibited a dose-dependent G2/M arrest. No arrest in G1 was seen. A strong correlation was found between the G2/M arrest and the induction of apoptosis. PA-1, the only cell line found to express wild-type p53, showed the highest susceptibility to accumulate in G2/M and the strongest apoptotic response after irradiation. In this cell line irradiation resulted in an unequivocal accumulation of p53 protein and in an increased expression of Bax protein. Caov-3, lacking wild-type p53, showed upregulation of Bax expression after irradiation. Caov-3 proved to be relative sensitive to apoptosis compared to SK-OV-3 and ES-2. These two cell lines were found to be p53 mutated in sequence analysis and irradiation had no effect on the expression of p53. No change in Bax expression was seen in ES-2, while SK-OV-3 exhibited decreased Bax protein levels after irradiation. Our data suggest that the G2/M arrest is an important component of the pathway leading from irradiation-induced DNA damage to apoptosis in the examined cell lines. The G2/M arrest and associated apoptosis found in the examined cell lines does not necessarily require wild-type p53, although wild-type p53 and possibly Bax may contribute to a maximum response to irradiation. Two independent mechanisms, p53-dependent and p53-independent, are suggested in the examined cell lines.
 ...
PMID:Role of p53 in G2/M cell cycle arrest and apoptosis in response to gamma-irradiation in ovarian carcinoma cell lines. 1246 84

The ability of p53 to alter, at the transcriptional level, the gene expression of downstream targets is critical for its role as a tumor suppressor. Most models of p53 activation postulate the stepwise recruitment by p53 of coactivators, histone acetyltransferases, and/or chromatin remodeling factors to a promoter region to facilitate the subsequent access of the general transcriptional machinery required for transcriptional induction. We demonstrate here, however, that the promoter regions for the p53 target genes, p21, 14-3-3sigma, and KARP-1, exist in a constitutively open conformation that is readily accessible to DNase I. This conformation was not altered by DNA damage or by whether p53 was present or absent in the cell. In contrast, p53 response elements, which resided outside the immediate promoter regions, existed within DNase I-resistant chromatin domains. Thus, p53 activation of downstream target genes occurs without p53 inducing chromatin alterations detectable by DNase I accessibility at either the promoter or the response element. As such, these data support models of p53 activation that do not require extensive chromatin alterations to support cognate gene expression.
 ...
PMID:Constitutive DNase I hypersensitivity of p53-regulated promoters. 1247 92

The ATR kinase phosphorylates both p53 and Chk1 in response to extreme hypoxia (oxygen concentrations of less than 0.02%). In contrast to ATR, loss of ATM does not affect the phosphorylation of these or other targets in response to hypoxia. However, hypoxia within tumors is often transient and is inevitably followed by reoxygenation. We hypothesized that ATR activity is induced under hypoxic conditions because of growth arrest and ATM activity increases in response to the oxidative stress of reoxygenation. Using the comet assay to detect DNA damage, we find that reoxygenation induced significant amounts of DNA damage. Two ATR/ATM targets, p53 serine 15 and histone H2AX, were both phosphorylated in response to hypoxia in an ATR-dependent manner. These phosphorylations were then maintained in response to reoxygenation-induced DNA damage in an ATM-dependent manner. The reoxygenation-induced p53 serine 15 phosphorylation was inhibited by the addition of N-acetyl-l-cysteine (NAC), indicating that free radical-induced DNA damage was mediated by reactive oxygen species. Taken together these data implicate both ATR and ATM as critical roles in the response of hypoxia and reperfusion in solid tumors.
 ...
PMID:ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. 1251 69

Histone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of hydroxamic acid-based HDAC inhibitors, in cell lines and patient cells from B-cell malignancies, including multiple myeloma (MM) and related disorders. SAHA induced apoptosis in all tumor cells tested, with increased p21 and p53 protein levels and dephosphorylation of Rb. We also detected cleavage of Bid, suggesting a role for Bcl-2 family members in regulation of SAHA-induced cell death. Transfection of Bcl-2 cDNA into MM.1S cells completely abrogated SAHA-induced apoptosis, confirming its protective role. SAHA did not induce cleavage of caspase-8, -9, or -3 in MM.1S cells during the early phase of apoptosis, and the pan-caspase inhibitor ZVAD-FMK did not protect against SAHA. Conversely, poly(ADP)ribose polymerase (PARP) was cleaved in a pattern indicative of calpain activation, and the calpain inhibitor calpeptin abrogated SAHA-induced cell death. Importantly, SAHA sensitized MM.1S cells to death receptor-mediated apoptosis and inhibited the secretion of interleukin 6 (IL-6) induced in bone marrow stromal cells (BMSCs) by binding of MM cells, suggesting that it can overcome cell adhesion-mediated drug resistance. Our studies delineate the mechanisms whereby HDAC inhibitors mediate anti-MM activity and overcome drug resistance in the BM milieu and provide the framework for clinical evaluation of SAHA, which is bioavailable, well tolerated, and bioactive after oral administration, to improve patient outcome.
 ...
PMID:Molecular sequelae of histone deacetylase inhibition in human malignant B cells. 1253 99

Within minutes of the induction of DNA double-strand breaks in somatic cells, histone H2AX becomes phosphorylated at serine 139 and forms gamma-H2AX foci at the sites of damage. These foci then play a role in recruiting DNA repair and damage-response factors and changing chromatin structure to accurately repair the damaged DNA. These gamma-H2AX foci appear in response to irradiation and genotoxic stress and during V(D)J recombination and meiotic recombination. Independent of irradiation, gamma-H2AX occurs in all intermediate and B spermatogonia and in preleptotene to zygotene spermatocytes. Type A spermatogonia and round spermatids do not exhibit gamma-H2AX foci but show homogeneous nuclear gamma-H2AX staining, whereas in pachytene spermatocytes gamma-H2AX is only present in the sex vesicle. In response to ionizing radiation, gamma-H2AX foci are generated in spermatogonia, spermatocytes, and round spermatids. In irradiated spermatogonia, gamma-H2AX interacts with p53, which induces spermatogonial apoptosis. These events are independent of the DNA-dependent protein kinase (DNA-PK). Irradiation-independent nuclear gamma-H2AX staining in leptotene spermatocytes demonstrates a function for gamma-H2AX during meiosis. gamma-H2AX staining in intermediate and B spermatogonia, preleptotene spermatocytes, and sex vesicles and round spermatids, however, indicates that the function of H2AX phosphorylation during spermatogenesis is not restricted to the formation of gamma-H2AX foci at DNA double-strand breaks.
 ...
PMID:DNA double-strand breaks and gamma-H2AX signaling in the testis. 1253 28


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>