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)

Cyclopentenone prostaglandins inhibit virus replication in several DNA and RNA virus models. In this report we investigated the effect of prostaglandin A1 (PGA1) on HIV-1 transcription in human CD4+ Jurkat T lymphocyte cells. A dramatic reduction of HIV-1 RNA levels was detected up to seven days post infection in both unstimulated and phorbol 12-mystrate 13-acetate (PMA)-stimulated cells treated with PGA1- PGA1 treatment of cells was also effective in inhibiting the transcription of a chloramphenicol acetyltransferase (CAT) reporter gene, under the control of HIV-1 LTR, in Jurkat-Tat cells. We also show that PGA1 induced the synthesis of 70-kDa heat-shock protein (HSP70) in this cell system and the induction correlated with the drug-antiviral activity. PGA1 was also found to induce the loss of the tumor suppressor p53 protein, in the "proliferative" conformation, in a time correlation with the induction of the HSP70 As the "proliferative" p53 has been involved in the positive trans-activation of the HIV-1 LTR its depletion could contribute to the inhibitory mechanisms of PGA1 on virus transcription.
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PMID:Inhibition of HIV-1 transcription by cyclopentenone prostaglandin A1 in Jurkat T lymphocytes. 1103 55

A retroviral vector containing wild-type p53 tumor suppressor gene (wt-p53) under the control of viral LTR sequences was constructed and transfected into packaging cell line GP+envAm12. Virus producing single cell clone GP+envAm12/ p53clC8 (8 x 10(5) cfu/ml, determined on NIH 3T3 cells) was isolated and used to transfer wt-p53 gene into human glioma cell lines in vitro. Decreased viability in p53-infected cells as compared to uninfected or empty virus infected cells was observed.
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PMID:Retrovirus vector containing wild type p53 gene and its effect on human glioma cells. 1104 23

The human papillomaviruses (HPV)-16 and HPV-18 referred to as high-risk HPVs are strongly associated with anogenital malignancies as well as benign epithelial cysts. It has been demonstrated that transgenic mice carrying HPV-16 E6-E7 under the control of the MMTV LTR developed malignant tumors including salivary gland carcinoma, lymphoma, skin histiocytomas and testicular tumors in a non-mammary gland specific manner. Another regulatory unit of rat beta-casein gene can confer the expression of fusion gene preferentially in the mammary glands of transgenic mice in a developmentally regulated manner. In order to generate mammary tumor formation in transgenic mice directing HPV16E6 gene alone into the mammary gland, this regulatory unit was fused to the E6 gene of HPV-16 type to constructing fusion gene. By screening 51 newborn founder transgenic mice, three mice carrying transgenes were identified. One line termed TG32 developed in a mammary gland tumor with large subcutaneous mass in the left rib region at 17 months of age. The levels of E6 transcript in the mass-tumor of TG32 line were lower than those in non-tumor mammary gland of identical TG32 and of TG250. In each tissue of TG32 line, high expression of E6 transcript was detected both in the mammary gland and brain. Histological analysis showed that cells from mammary gland tumor of the TG32 line had also hyperplasia appearance, with irregular or increased total number of mitotic rate. These observations suggest that developing phenotype and the level of E6 transcripts in the process of malignant transformation may have different mechanisms involving the capacity to bind and destabilize p53, although for confirmation it is necessary to investigate many more transgenic mice.
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PMID:Mammary gland tumor in transgenic mice expressing targeted beta-casein/HPV16E6 fusion gene. 1107 93

Many mutants of p53 activate HIV-LTR driven transcription and promote HIV replication. The region of the HIV-LTR containing Sp1-binding sites is important for this effect. In this study we test the hypothesis that mutant p53 interacts with DNA-bound Sp1 and in this way can increase transcription from Sp1-dependent promoters. We have used the breast cancer cell line MDA-MB-468 that expresses endogenous mutant p53(His273) as our source of p53 protein. First, we demonstrated that this mutant p53 participates in activating transcription from the HIV-LTR by showing that HIV-LTR-directed transcription in MDA-MB-468 cells is inhibited in a dominant-negative manner by p53(Val135). Using HIV-LTR DNA affinity chromatography, we detected coelution of p53(His273) and Sp1. We also demonstrated that this mutant p53 binds sequence specifically to the super consensus sequence (SCS) and that Sp1 coeluted with p53(His273) from a column containing this site. These data indicate that p53(His273) can associate with DNA-bound Sp1 suggesting that activated HIV-LTR transcription associated with mutant p53 occurs through a DNA driven multi-protein complex.
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PMID:Mutant p53 forms a complex with Sp1 on HIV-LTR DNA. 1111 96

Glucocorticoid hormones are known to enhance gonadotropin/cAMP-induced steroidogenesis in rat and human granulosa cells. As glucocorticoids induce apoptosis in numerous cell types, we investigated the role of glucocorticoids in the control of apoptosis in immortalized human granulosa cells (HO-23) transfected with a temperature-sensitive mutant of p53 (Val(135)). When HO-23 were incubated with forskolin in the presence or absence of dexamethasone (Dex) at 32 or 37 C, progesterone production was higher by 4- and 8-fold in the presence of Dex at 37 or 32 C, respectively (P: < 0. 01). The expression of adrenodoxin (ADX), which is an intrinsic part of the cytochrome P450 side-chain cleavage enzyme system, remained the same in the presence or absence of Dex in forskolin-stimulated cells. Dex reduced apoptosis (to 33% of control) in cultures after activation of p53 by shifting the temperature from 37 to 32 C. Moreover, Dex suppressed apoptosis induced by serum deprivation (to 40% of control) or forskolin stimulation (to 28% and 40% at 37 and at 32 C, respectively). The protective effect of Dex on cAMP-, p53-, and serum deprivation-induced apoptosis was confirmed by both 4',6-diamido-2-phenylindole hydrochloride DNA staining and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling with an ED(50) of 7 nM Dex. Hydrocortisone showed a similar antiapoptotic effect. The protective effect of glucocorticoids against apoptosis was completely abolished by RU486 when cells were coincubated with 10 nM Dex and 10-100 nM RU486. The protection against apoptosis by glucocorticoid involved a sharp elevation in intracellular levels of Bcl-2 (3-7.6 fold; P: < 0.01). In contrast to the effect of Dex in the prevention of apoptosis in HO-23 granulosa cells, Dex dramatically stimulated apoptosis by 3-fold in LTR-6 myeloid leukemia cells expressing the same temperature-sensitive mutant (Val(135) p53) and the same amount of glucocorticoid receptor-alpha. Forskolin did not stimulate apoptosis when incubated with these cells. However, it augmented by 1.2-fold the p53-induced apoptosis in cells shifted from 37 to 32 C. Dex further enhanced apoptosis by 1.9-fold in p53-activated cultures (32 C). Incubation of the cells with Dex dramatically reduced Bcl-2 levels to 15% of control at 37 C (P: < 0.01) or 32 C in the presence or absence of forskolin (P: < 0.01). Our data suggest that glucocorticoids exert a protective effect against induced apoptosis in immortalized granulosa cells and a stimulatory effect on apoptosis in myeloid leukemia cells. Moreover, modulation of Bcl-2 levels plays an important role in mediating the glucocorticoid effect on cell survival. The opposite effect of glucocorticoids on Bcl-2 levels in the two cell lines may be due to the different ontogeneses of the two cell types: epithelial for granulosa cells vs. mesenchymal for myeloid cells studied in the present work.
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PMID:Glucocorticoids protect against apoptosis induced by serum deprivation, cyclic adenosine 3',5'-monophosphate and p53 activation in immortalized human granulosa cells: involvement of Bcl-2. 1115 53

p73 has been shown to transcriptionally activate genes positively responsive to wild-type p53. In order to undertake a comparative study of functions of p53 and p73 we have cloned the cDNA of p73 from MCF-7 cells. Adenovirus onco-protein E1A inhibits the transactivation by p73; a deletion mutant of E1A incapable of interacting with p300 and CREB-binding protein (CBP) fails to disrupt the transactivation. Furthermore, CBP increases the transactivation mediated by p73 suggesting that CBP may function as a co-activator and E1A inhibits p73-mediated transactivation by sequestering p300 or CBP. We show that p73 can transcriptionally inhibit a number of cellular and viral promoters. However, wild-type p53, p73 alpha and p73 beta differ in their ability to inhibit transcriptional activity of different promoters. While wild-type p53 inhibits the promoters of the human cytomegalovirus (CMV) immediate-early gene, the long terminal repeat of human immunodeficiency virus type 1 (HIV LTR), human cyclin A (cyc A) gene, and insulin-like growth factor receptor I (IGF-I-R), p73 alpha only inhibits the HIV LTR and cyc A promoters significantly; and p73 beta inhibits the CMV, HIV LTR and cyc A promoters. A mutant of p73 alpha having amino acid substitutions at positions 268 and 300 on the presumptive DNA-binding domain fails to transactivate the p21 promoter but represses the CMV and the HIV LTR promoter quite efficiently showing that the mechanisms of transactivation and repression by p73 are different. Interestingly, p73 alpha transactivates the IGF-I-R promoter, which is inhibited by wild-type p53; p73 beta has no significant effect on this promoter. This is a unique situation where p73 alpha differs from p73 beta as well as p53.
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PMID:Differential modulation of cellular and viral promoters by p73 and p53. 1117 10

Considerable progress has been made in the transfer of foreign genes into salivary glands in vivo using adenovirus vectors in rats. In an attempt to avoid the transient expression inherent, when using these vectors, retroviral vectors and human cell lines where used here in attempt to develop an in vitro model of HIV-associated salivary gland disease. The HIV-1-tat protein is increasingly implicated in the pathogenesis of the AIDS through altering the expression of strategic cellular genes. The purpose of this study was to transfect human salivary gland (HSG) cell lines in vitro, with the pHIV-1/LTR-tat plasmid, and examine the effect of tat on expression of matrix and basement membrane genes known to be important in the pathogenesis of salivary gland disease. HSG cells were transfected with HIV-1-tat plasmid by the lipofection method. Transfection was confirmed by polymerase chain reaction (PCR) and Southern blot, which verified that tat-specific DNA was present. Tat-mRNA was analysed by Northern blotting and quantified by reverse transcriptase polymerase chain reaction (RT-PCR) to demonstrate its expression. Numerous clones were found to contain integrated tat DNA sequences and analysis of mRNA showed stable expression of tat-specific RNA. Further analysis of mRNA expression for various marker proteins important in HIV pathogenesis showed that the HSG cell line transfected with HIV-1-tat, was associated with significant induction of mRNA expression for extracellular matrix protein. Tat-amplified transcription of the major basement membrane protein laminin, as well as of fibronectin, collagen I and III, and c-myc oncogene was demonstrated. Conversely, expression of p53 suppressor gene mRNA was reduced. Post-transfection expression of collagen IV was erratic and inconclusive. It was concluded that the presence of HIV-tat in this in vitro model of salivary ductal epithelial cell model alters the mRNA expression of several matrix, basement membrane and oncoproteins known to be involved in HIV pathogenesis. These cell lines provide a useful system for studying the role of tat in the immunopathogenesis of HIV-associated salivary gland disease.
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PMID:Amplification of extracellular matrix and oncogenes in tat-transfected human salivary gland cell lines with expression of laminin, fibronectin, collagens I, III, IV, c-myc and p53. 1131 Dec 2

HTLV-I is causually related to the oncogenesis of adult T cell leukemia (ATL). However, the precise mechanism of HTLV-I oncogenesis is unclear. HTLV-I Tax protein functions as an activator of various cellular genes, including IL-2, IL-2 receptor-alpha, and c-fos through the activation of nuclear transfer factors such as NF-kappaB and SRF, and also potently activates trascription of viral genes through CREB/ATF sites in the viral LTR. However, Tax activation of HTLV-I infected T cells through the above pathways induces polyclonal proliferation of the cells in vitro; Tax however may function only transiently in the immediate post-infection period following infection in vivo. The long latent period of 60 years from infection to onset of disease suggests other mechanisms for ATL oncogenesis. Recent studies suggest that the malignant transformation of ATL is a multi-hit phenomena, suggesting that discrete genetic events are responsible for ATL oncogenesis. These genetic events could be responsible for the different stages of ATL: smoldering, chronic, lymphoma, and acute type, p16 and p53 genes are important negative regulators of the cell cycle and are often found to be mutated in neoplasms. Recent studies including ours demonstrated a high frequency of alteration of these two genes in primary ATL cells. Furthermore, alteration of the two genes is associated with acute but not chronic type ATL. In addition, p16 gene alteration is linked to the growth rate of ATL cells, suggesting that the alteration of these cell cycle regulatory genes may be related to progression from smoldering or chronic to acute or lymphoma type ATL. Tax may be involved in mutagenesis of these genes through suppression of DNA-beta polymerase gene expression during the process from latent period to acute/lymphoma type. Once transformation occurs, activation of the pathway between Tax and the three nuclear transfer factors, NF-kappaB, SRF, and CREB/ATF, contributes to establish the aggressive manifestations of acute/lymphoma type ATL cells.
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PMID:HTLV-I Tax related dysfunction of cell cycle regulators and oncogenesis of adult T cell leukemia. 1142 48

In a previous study we reported that methylation within the promoter region of p53 was altered in human lung A549 cells exposed to arsenite over a 2-week period in culture. In the present study the methylation status of the 5' control region of the tumor suppressor gene, von Hippel Lindau syndrome (VHL), a gene known to be silenced transcriptionally by CpG methylation was assessed. No changes in DNA methylation in VHL in human kidney UOK cell lines exposed to arsenite were seen after 4 weeks in culture, assessed by simple HpaII digestion followed by PCR amplification. Using methylation-sensitive arbitrarily-primed PCR we identified eight differentially methylated regions of genomic DNA of approximately 300--500 bp from three UOK cell lines and from human lung A549 cells after arsenite exposure in culture. Six fragments were hypermethylated, and two were hypomethylated, relative to untreated controls. Sequence analysis revealed two DNA fragments contained repeat sequences of mammalian-apparent LTR retrotransposons, five contained promoter-like sequences, and 13 CpG islands were identified. Three fragments had 99-100% homology to regions on human chromosomes 6, 9, and 15 but these genes have not yet been identified. Our findings are consistent with a potential role for both hypermethylation and hypomethylation of DNA that coexist after exposure to arsenite. The results, in total, could support the existence of a state of DNA methylation imbalance that could conceivably disrupt appropriate gene expression in arsenite exposed cells.
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PMID:Both hypomethylation and hypermethylation of DNA associated with arsenite exposure in cultures of human cells identified by methylation-sensitive arbitrarily-primed PCR. 1148 57

Full-length human p53 protein was examined using tryptophan fluorescence and circular dichroism spectroscopy (CD) to monitor unfolding. No significant alteration in tryptophan fluorescence for the tetrameric protein was detectable over a wide range of either urea or guanidine hydrochloride concentrations, in contrast to results with the isolated DNA binding domain [Bullock et al. (1997) Proc. Natl. Acad. Sci. USA 94, 14338]. Under similar denaturant conditions, CD demonstrated significant protein unfolding for the full-length wild-type protein, with increased apparent structure loss compared to that detected during thermal denaturation [Nichols and Matthews (2001) Biochemistry 40, 3847]. Examination of X-ray structures containing two of the four tryptophan residues of a p53 monomer suggested local environments consistent with quenched fluorophores. Exploration of p53 fluorescence using potassium iodide as a quencher confirmed that these fluorophores are already substantially quenched in the native structure, and this quenching is not relieved during protein unfolding.
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PMID:p53 unfolding detected by CD but not by tryptophan fluorescence. 1159 60


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