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)

Leukoplakia has evolved as a clinico-pathologic concept over many years, with the current clinical designation being accepted worldwide. Reflective of the biology of leukoplakia is the concept of cellular atypia and epithelial dysplasia. Adding to a better understanding of leukoplakia in general has been the definition of relevant clinical subsets which, in some cases, includes etiology (snuff), while in other cases a verrucous clinical appearance will suggest a more aggressive anticipated behavior pattern. Tobacco usage, in many of its forms, remains the prime etiologic factor; however, other considerations also apply. More recently, the potential etiologic role of Candida albicans has been stressed, as well as its possible role in carcinogenesis. So-called oral hairy leukoplakia has been defined in relation to a possible Epstein-Barr viral infection, usually in the immunosuppressed patient. Other viruses, human papilloma virus in particular, have been implicated in leukoplakia, while genetic alterations involving tumor suppressor elements (p53) have also been investigated. Finally, the management of this common condition remains a variable and includes local, topical, and systemic therapies such as anti-oxidants, carotenoids, and retinoids.
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PMID:Oral leukoplakia. 754 21

The purpose of this study was to characterize the clinical and histological features of intraoral squamous cell carcinoma in men who were seropositive for the human immunodeficiency virus and to evaluate viral cofactors (human papillomavirus, herpes simplex virus, Epstein-Barr virus), proliferative index (proliferating cell nuclear antigen), a factor associated with invasion (cathepsin D), and mutated tumor suppressor gene and proto-oncogene products (mutated p53, c-erbB-2). Four men who were seropositive for the human immunodeficiency virus and had acquired immunodeficiency syndrome presented with painful oral lesions of variable duration. Oral cancer risk factors included heavy tobacco use (four of four), heavy alcohol use (three of four), and previous radiotherapy (one of four). The lesions consisted of ulcers (two of four), a fungating mass (one of four), and papillary erythroplakia (one of four). Incisional biopsy specimens were obtained. High-stringency in situ hybridization was performed with DNA probes to the human papillomavirus (types 6/11; 16/18; 31/33/35) and Epstein-Barr virus: Immunocytochemical studies for the herpes simplex virus, proliferating cell nuclear antigen, cathepsin D, mutated p53, and c-erbB-2 were performed. Two lesions were moderately differentiated squamous cell carcinoma, one lesion was a basaloid squamous cell carcinoma, and one was carcinoma in situ. Stage of disease at diagnosis was II (one of four), III (two of four), and IV (one of four). Three cases were positive for the human papillomavirus, one case was positive for Epstein-Barr virus, and three cases were positive for the herpes simplex virus. C-erbB-2 was focally positive in one case, and mutated p53 was positive in a separate case.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intraoral squamous cell carcinoma in human immunodeficiency virus infection. A clinicopathologic study. 755 63

The EBNA-LP protein (also known as EBNA-5) of Epstein-Barr virus (EBV) has been reported previously to colocalize in the nuclei of cells with the pRb protein and to bind in vitro to pRb and to the p53 protein, suggesting a role for EBNA-LP in modulation of the function of these proteins. Here we test in transfection assays whether EBNA-LP expression has any functional consequence for repression of E2F-1 activity by pRb or p107 or for activation of transcription by the p53 protein. No significant effect could be found, although the assay systems were sensitive to the established effects of simian virus 40 large T antigen and human papillo-mavirus type 16 E6 protein. There was very effective repression of GAL4/E2F-1 transactivation by p107, consistent with earlier reports and indicating that p107 can interact with the E2F-1 transactivation domain, even though p107 has been reported to bind specifically to E2F complexes containing E2F-4. The results indicate that, if the associations of EBNA-LP with pRB and p53 are physiologically relevant, they most likely affect other functions of these proteins or modulate their gene regulatory functions in ways that cannot be detected by transfection into cycling transformed cells.
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PMID:Epstein-Barr virus EBNA-LP and transcription regulation properties of pRB, p107 and p53 in transfection assays. 756 51

We have previously shown that exogenous wild type p53 induces apoptosis in the Burkitt lymphoma line BL41 that carries endogenous mutant p53, using a temperature sensitive p53 construct expressed as mutant p53 at 37 degrees C and wild type p53 at 32 degrees C (Ramqvist et al., Oncogene, 8, 1495-1500, 1993). We also found that wild type p53-induced apoptosis is blocked by bcl-2 in a mouse T lymphoma line (Wang et al., Oncogene, 8, 3427-3431, 1993) The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) can protect Burkitt lymphoma cells from apoptosis induced by low serum. In order to test if LMP1 can block p53-triggered apoptosis, we infected BL41 cells expressing the ts p53 construct with an LMP1-carrying retrovirus. The LMP1-expressing BL41-ts p53 cells were arrested in G1 upon induction of wild type p53 expression at 32 degrees C, but did not enter apoptosis as shown by the absence of positive TUNEL staining. WAF1/p21 mRNA was induced at 32 degrees C in both the ts p53-expressing and ts p53/LMP1-expressing BL41 cells. Thus, LMP1 prevents p53-induced apoptosis but does not interfere with induction of WAF1/p21. The LMP1-infected cells expressed elevated bcl-2 protein levels. Therefore, our data suggest that LMP1 blocks p53-triggered apoptosis but not G1 arrest by upregulating bcl-2 expression.
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PMID:The EBV-encoded LMP1 protein inhibits p53-triggered apoptosis but not growth arrest. 756 60

Cisplatin treatment of Epstein-Barr virus-immortalized human B lymphoblastoid cell lines (LCLs) results in p53-mediated apoptosis which occurs largely in a population of cells at the G1/S boundary of the cell cycle. Cell cycle progression appears to be required for this apoptosis because arresting cells earlier in G1 inhibited apoptosis despite the accumulation of p53. Overexpression of wild-type p53 also induces apoptosis in an LCL. Therefore six mutant genes derived from Burkitt's lymphoma (BL) cells were assayed for their ability to induce apoptosis when similarly overexpressed. The same genes were analysed in transient transfection assays for their ability to transactivate appropriate reporter plasmids. A correlation between the ability of p53 to transactivate and induce apoptosis was revealed. The only mutant capable of transactivation also induced apoptosis. Further analysis of the BL lines in which p53 had been characterized showed that whereas some lines were essentially resistant to cisplatin, three were rapidly induced to undergo apoptosis. All three have a single p53 allele encoding a mutant which is incapable of transactivation or (for two tested) mediating apoptosis when expressed in an LCL. Cell cycle analysis revealed that this apparently p53-independent apoptosis did not follow G1 arrest but in fact occurred largely in cells distributed in the G2/M phase of the cell cycle. These data suggest the existence of a second checkpoint in the G2 or M phase which, in the absence of a functional p53, is the primary point of entry into the apoptosis programme following DNA damage.
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PMID:DNA damage in human B cells can induce apoptosis, proceeding from G1/S when p53 is transactivation competent and G2/M when it is transactivation defective. 758 28

Epstein-Barr virus (EBV) efficiently converts resting human B cells into actively cycling, immortal, lymphoblastoid cell lines (LCLs). Here we show that LCLs expressing the full complement of latent viral genes are very sensitive to DNA-damaging agents such as cisplatin. The response includes a rapid accumulation of the tumour suppressor protein p53 and induction of the cellular genes mdm2 and WAF1/p21. Although the levels of Bcl2 protein and Bax mRNA appear unaltered by the activation of p53, within 24 h the majority of cells undergo apoptosis. Over-expression of wild-type p53 in an LCL also resulted in apoptosis; this was preceded by the dephosphorylation of the retinoblastoma gene product, pRb. Primary resting B cells showed no response to cisplatin and even after drug treatment, p53 remained undetectable. However, after infection with EBV, p53 gene expression was induced to a similar level to that found in mitogen-activated B cells. When the physiologically activated primary B cells were exposed to cisplatin, although p53 accumulated as in LCLs, the outcome was growth-arrest rather than gross cell death. We conclude that, in contrast to the transformation of fibroblasts by adenovirus, SV40 or HPV, when B cells become activated and immortalized by EBV they are sensitized to the p53-mediated damage response. When the resulting LCLs are treated with genotoxic agents such as cisplatin, they are unable to arrest like normal cells because they are driven to proliferate by EBV and consequently undergo apoptosis.
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PMID:Epstein-Barr virus efficiently immortalizes human B cells without neutralizing the function of p53. 772 16

In patients infected with HIV, high-grade B-cell non-Hodgkin's lymphomas (NHL), including the small noncleaved cell (SNCC) category, exhibit pleomorphic features, which makes precise definition difficult. Sixty-nine pathologic specimens with HIV-related systemic lymphomas, including 42 SNCC, 20 immunoblastic lymphomas (IBL), and 7 cases with features "intermediate" between SNCC and IBL were morphologically and immunophenotypically investigated. The host immune status was also analyzed in 57 of 69 patients. In 29 representative SNCC lymphomas, in 9 IBL cases, and an additional 3 intermediate lymphomas, both p53 protein overexpression and the association of Epstein-Barr virus (EBV) genetic information were assessed. Small noncleaved cell lymphomas included tumors exhibiting features of the 2 established subtypes (27 Burkitt's and 15 non-Burkitt's). In the seven intermediate cases, cells showed features intermediate between SNCC with plasmablastic differentiation and immunoblasts plasmacytoid. Immunoblast-like cells were also present. p53 protein overexpression and EBV association were found in a proportion of SNCC (14 of 29; 7 of 29) and intermediate (3 of 3; 2 of 3) lymphomas. Conversely, IBL cases were consistently p53 negative, but showed a high EBV association (7 of 9). All the evaluated patients with intermediate lymphomas had a considerably lower mean (76.6 per mm3 +/- 77.4 SD) and median (54 per mm3) number of CD4+ lymphocyte count than SNCC patients (mean 227.9 per mm3 +/- 186.9 SD, median 193 per mm3), thus mirroring IBL patients (mean 95.3 per mm3 +/- 82.8 SD, median 81 per mm3). All data provide evidence that lymphomas showing intermediate features constitute a distinct subgroup from either SNCC or IBL.
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PMID:AIDS-related Burkitt's lymphoma. Morphologic and immunophenotypic study of biopsy specimens. 774 Nov

Epstein-Barr virus/C3d receptor (CR2, CD21) interacts with three intracellular proteins: the p53 anti-oncoprotein expressed in human B lymphoma cells, the p68 calcium binding protein expressed in normal B lymphocytes and the nuclear p120 ribonucleoprotein (RNP). We previously demonstrated that p53 and p68 interacted with the intracytoplasmic carboxy-terminal domain of CR2. To analyse the amino acid sequence of CR2 binding sites for p53 and p68, we synthesized different peptides whose sequences were derived from this carboxy-terminal domain. Thus, CR2 bound to p53 and p68 through two distinct binding sites localized on the N-terminal and on the central part of its carboxy-terminal domain, characterized by the amino acid sequences of KHRERNYYTD and KEAFHLEARE, respectively. CR2 site reacting with the nuclear p120RNP was determined using either anti-CR2 mAb directed against its extracellular domain or pep34, pep14/SCR3 and pep14/SCR4, synthetic peptides whose sequences corresponded to the intracellular 34 amino acid domain or to sites of the extracellular domain of CR2, respectively. Data support that CR2 interacts with p120RNP through the DEGYRLQGPPSSRC amino acid sequence of its extracellular SCR4 domain. Furthermore, phosphorylation of CR2 inhibits its interaction with the nuclear p120RNP. Binding of CR2, through its intracellular and extracellular domains, with the p53 oncoprotein and p120RNP, respectively, and the co-localization of these three proteins on nuclear interchromatin fibrils, suggest that CR2 could act as a crosslinker between these two nuclear proteins to regulate their functions.
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PMID:Binding sites of the Epstein-Barr virus and C3d receptor (CR2, CD21) for its three intracellular ligands, the p53 anti-oncoprotein, the p68 calcium binding protein and the nuclear p120 ribonucleoprotein. 775 47

When deprived of autocrine growth factors, Epstein-Barr virus (EBV)-immortalized B cells stop growing and die. In this study, we show that death of EBV-immortalized cells deprived of autocrine growth factors occurred by apoptosis. Cycloheximide, a protein synthesis inhibitor, inhibited apoptosis, suggesting that de novo protein synthesis is required. Because p53, Bcl-2, and c-Myc were previously implicated in the induction or prevention of apoptosis in other systems, we assessed their possible involvement here. Unlike normal cells that respond to growth factor deprivation by down-regulating c-Myc expression, EBV-immortalized cells continued to express c-Myc, p53, and Bcl-2 at levels comparable to those measured prior to starvation. Consistent with data demonstrating that c-Myc expression is sufficient to drive quiescent cells into the cell cycle, autocrine growth factor-deprived EBV-immortalized cells did not undergo growth arrest but rather continued to proliferate until death, which occurred randomly throughout the cell cycle. In contrast to EBV-immortalized B cells, normal peripheral blood B cells activated in vitro with anti-CD40 monoclonal antibody and interleukin 4 rapidly down-regulated c-Myc expression and underwent growth arrest in response to growth factors and serum deprivation. These findings demonstrated that c-Myc expression is deregulated in EBV-immortalized cells. Addition of antisense oligonucleotides to c-Myc specifically promoted the survival of starved EBV-immortalized cells and suppressed growth of nonstarved EBV-immortalized cells. Thus, deregulated expression of c-Myc in EBV-immortalized cells promotes proliferation and apoptosis following autocrine growth factor deprivation.
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PMID:A role for deregulated c-Myc expression in apoptosis of Epstein-Barr virus-immortalized B cells. 780 56

We investigated 34 cases of T-cell neoplasm [15 cases of T-cell granular lymphocytic leukemia (T-GLL), 10 cases of T-cell non-Hodgkin's lymphoma (T-NHL), six cases of T-cell chronic lymphocytic leukemia (T-CLL), and three cases of cutaneous T-cell lymphoma] to study their association with Epstein-Barr virus (EBV). In 4 (three T-NHL and one T-GLL) of 34 cases, EBV genome was detected in a single episomal form, while polyclonal EBV-DNA was detected in one (T-NHL) of the remaining cases. All three cases of T-NHL having monoclonal EBV episome showed histologically diffuse large-cell lymphoma and developed leukemic conversion. Phenotypic analysis showed that two of these four cases were CD4+, CD8-, and the remaining two cases were CD4-, CD8+. The cells from all four cases were confirmed to be in T-cell lineage by detecting the rearrangement of T-cell receptor (TCR) beta or gamma chain gene. By reverse transcription-polymerase chain reaction (RT-PCR), EBNA-1 was detected at low levels, and neither EBNA-2 nor LMP-1 were found in any of the three cases examined. Lack of the expression of EBNA-2 and LMP-1 was also confirmed by immunocytochemical staining. The cells of these four cases did not show rearrangement or overexpression of c-myc and bcl-2 genes by Southern and Northern blots, and the mutation of p53 gene was detected in only one patient. These results suggest that other latent gene products of EBV or other cellular oncogenes are involved in the development of Japanese T-cell neoplasm after EBV infection.
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PMID:Lack of the expression of EBNA-2 and LMP-1 in T-cell neoplasms possessing Epstein-Barr virus. 781 2


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