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)

Infection with human immunodeficiency virus type 1 (HIV-1) is associated with dramatic depletion of CD4(+) T cells, the major HIV-1-induced pathogenesis. Apoptosis has been suggested to play an important role for the T cell depletion and a number of mechanisms have been proposed for the apoptosis in T cells. Here, we compared the levels for apoptosis induction in primary peripheral blood mononuclear cells (PBMCs) among several laboratory strains and primary isolates of the HIV-1 subtypes B and E. The results showed that apoptosis in infected PBMCs, preferentially in CD4+ T cell population, became detectable around the time for virus production by flow cytometric terminal transferase dUTP nick end labeling (TUNEL) technique and staining with the nuclear dye Hoechst 33342. The abilities to induce apoptosis in PBMCs were highly variable in individual isolates. The increase of p53 protein in infected PBMCs, which was initiated before virus production, was observed in infected PBMCs and the levels of p53 protein were almost proportional to the rates of the isolates to induced apoptosis. The cells infected and cultured in the presence of Z-VAD-FMK had significantly decreased cell mortalities, indicating that activated caspases also played a significant role in the apoptosis. Thus, HIV-1-induced apoptosis in primary T cells was accompanied by the p53 protein and caspase activation at varied levels in primary isolates.
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PMID:Ability to induce p53 and caspase-mediated apoptosis in primary CD4+ T cells is variable among primary isolates of human immunodeficiency virus type 1. 1195 87

In the present study, epithelium derived lesions of various pathological manifestations were examined histologically and immunohistochemically for mononuclear cell infiltration. The infiltrate under the transformed epithelium of oral lesions, was examined for differences in the composition of immune mononuclear cells as the epithelium moves from hyperkeratosis through various degrees of dysplasia to squamous cell carcinoma. The study was performed on 53 human tongue tissues diagnosed as hyperkeratosis (11 cases), mild dysplasia (nine cases), moderate and severe dysplasia (14 cases) and squamous cell carcinoma (19 cases). A similar analysis was performed on 30 parotid gland tissues diagnosed as pleomorphic adenoma (14 cases) and carcinoma ex-pleomorphic adenoma (16 cases). Immunohistochemical analysis of various surface markers of the tumour infiltrating immune cells was performed and correlated with the transformation level as defined by morphology and the expression of p53 in the epithelium. The results revealed that, in the tongue lesions, the changes in the epithelium from normal appearance to transformed were accompanied by a corresponding increase in the infiltration of CD4, CD8, CD14, CD19+20, and HLA/DR positive cells. The most significant change was an increase in B lymphocytes in tongue lesions, that was in accordance with the transformation level (P<0.001). In the salivary gland, a significant number of cases did not show an infiltrate. In cases where an infiltrate was present, a similar pattern was observed and the more malignant tissues exhibited a higher degree of immune cell infiltration.
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PMID:Increase in immune cell infiltration with progression of oral epithelium from hyperkeratosis to dysplasia and carcinoma. 1198 79

Different vaccine constructs based on DNA vaccines and viral recombinant vaccines expressing mouse p53 were compared for induction of protective immune responses to challenge with a sarcoma cell line that expresses high levels of mutated p53 protein. Viral recombinant vaccines based on E1-deleted adenovirus or vaccinia virus recombinants expressing p53 with wild-type sequences in the mutational hotspot domain and a single mutation in the tetramerization domain (p53(mu338)) failed to induce protection against progression of this tumor cell line. A DNA vaccine expressing a form of p53 carrying the same point mutations as the tumor cell line showed low efficacy that was comparable to that of a DNA vaccine expressing p53(mu338). Efficacy of the DNA vaccine was augmented upon expressing p53(mu338) as a fusion protein linked to a viral leader sequence. Other modifications such as fusion to the signal sequence of the lysosome-associated membrane protein (LAMP) or ubiquitin failed to improve the efficacy of the vaccine to p53. Protection mediated by CD4(+) and CD8(+) T cells was specific for p53.
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PMID:A modified DNA vaccine to p53 induces protective immunity to challenge with a chemically induced sarcoma cell line. 1214 33

Syncytia arising from the fusion of cells expressing the HIV-1-encoded Env gene with cells expressing the CD4/CXCR4 complex undergo apoptosis following the nuclear translocation of mammalian target of rapamycin (mTOR), mTOR-mediated phosphorylation of p53 on Ser15 (p53(S15)), p53-dependent upregulation of Bax and activation of the mitochondrial death pathway. p53(S15) phosphorylation is only detected in syncytia in which nuclear fusion (karyogamy) has occurred. Karyogamy is secondary to a transient upregulation of cyclin B and a mitotic prophase-like dismantling of the nuclear envelope. Inhibition of cyclin-dependent kinase-1 (Cdk1) prevents karyogamy, mTOR activation, p53(S15) phosphorylation and apoptosis. Neutralization of p53 fails to prevent karyogamy, yet suppresses apoptosis. Peripheral blood mononuclear cells from HIV-1-infected patients exhibit an increase in cyclin B and mTOR expression, correlating with p53(S15) phosphorylation and viral load. Cdk1 inhibition prevents the death of syncytia elicited by HIV-1 infection of primary CD4 lymphoblasts. Thus, HIV-1 elicits a pro-apoptotic signal transduction pathway relying on the sequential action of cyclin B-Cdk1, mTOR and p53.
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PMID:Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the HIV-1 envelope. 1214 7

Overexpression of p53 is found in approximately 50% of human cancers, making it an attractive target antigen for immunotherapy of cancer. Research in this area has thus far primarily focused on p53-specific CTLs. Although these CTLs were shown to be highly effective against p53-overexpressing tumors in vivo, immunological tolerance seems to strongly restrict the spectrum of the p53-specific CTL repertoire in p53(+/+) subjects. In view of the emerging role of CD4(+) Th (Th) cells in the antitumor response, we investigated the specificity and antitumor efficacy of the p53-specific Th response in mice. Our data show that high affinity Th cells against the naturally processed epitope p53(108-122) can be elicited in both p53(-/-) and p53(+/+) mice, indicating that the p53-specific T-cell response is not affected by tolerance at the Th level. Furthermore, p53(108-122)-specific Th cells were effective in enabling p53-specific CTLs to control the growth of p53-overexpressing tumors in vivo. Therefore, exploitation of the p53-specific Th response appears to be a highly useful aspect of immunotherapeutic strategies against cancers.
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PMID:Antitumor efficacy of wild-type p53-specific CD4(+) T-helper cells. 1241 46

In order to study the response of T cells to IL-7, we aimed to generate an IL-7-dependent thymocyte line. CD4(-)CD8(-) thymocytes from a p53(-)/(-) mouse were continuously propagated in interleukin-7 (IL-7), and after 2 months there developed an immortal line termed "D1." The D1 line has retained a stable dependency on IL-7. Withdrawal of IL-7 from D1 cells induced arrest in G1 phase of the cell cycle, followed by apoptosis. In addition to IL-7, several other cytokines that employ gamma(c) as part of their receptor were also capable of stimulating D1 cell survival and proliferation. Gene induction by IL-7 was analyzed in D1 cells using RNase protection and array analysis and revealed a number of transcripts potentially involved in cell cycle, apoptosis and signaling.
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PMID:Characterization of an interleukin-7-dependent thymic cell line derived from a p53(-/-) mouse. 1260 43

p53 is overexpressed by half of all cancers, and is an attractive target for a vaccine approach to immunotherapy. p53 overexpression is frequently the result of point mutations, which leaves the majority of the protein in its wild-type form. Therefore, the majority of p53 sequence is wild type, making it a self-protein for which tolerance plays a role in limiting immune responses. To overcome tolerance to p53, we have expressed wild-type murine p53 in the nonpathogenic attenuated poxvirus, modified vaccinia virus Ankara (recombinant modified vaccinia virus Ankara expressing wild-type murine p53 (rMVAp53)). Mice immunized with rMVAp53 vaccine developed vigorous p53-specific CTL responses. rMVAp53 vaccine was evaluated for its ability to inhibit the outgrowth of the syngeneic murine sarcoma Meth A, which overexpresses mutant p53. Mice were inoculated with a lethal dose (5 x 10(5) cells injected s.c.) of Meth A tumor cells and vaccinated by i.p. injection 3 days later with 5 x 10(7) PFU of rMVAp53. The majority of mice remained tumor free and resistant to rechallenge with Meth A tumor cells. We wished to determine whether rMVAp53 immunization could effect the rejection of an established, palpable Meth A tumor. In subsequent experiments, mice were injected with 10(6) Meth A tumor cells, and treated 6 days later with anti-CTLA-4 Ab (9H10) and rMVAp53. The majority of treated mice had complete tumor regression along with lasting tumor immunity. In vivo Ab depletion confirmed that the antitumor effect was primarily CD8 and to a lesser extent CD4 dependent. These experiments demonstrate the potential of a novel cell-free vaccine targeting p53 in malignancy.
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PMID:CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model. 1262 1

Different biologic features have been associated with a more or less aggressive clinical course in chronic lymphocytic leukemia (CLL). In the present study, 20 patients with highly stable CLL observed at a single institution over a period of 10 to 23 years and who never required treatment were extensively characterized. The aim was to identify a distinct and reproducible biologic profile associated with disease stability that may be used to recognize at presentation CLL patients who are likely to have a very benign clinical course and for whom treatment is not indicated. The results obtained indicate that numerous parameters are closely associated with disease stability: a typical CLL morphology and immunophenotype, the lack of expression of the CD38 antigen, the mutated immunoglobulin (Ig) heavy (H) chain variable (V) pattern, the absence of p53 mutations, a CD4/CD8 ratio more than 1, the lack of 17p and 11q deletions and of complex karyotypic aberrations, and the occurrence of the 13q14 deletion. No case displayed the VH3-21 gene, linked in mutated CLL with a poor outcome. In addition, the VH1-69 gene associated with unmutated CLL cases was never detected. These biologic features were coupled with an indolent clinical course characterized by an unmodified clinical stage over time, and by lack of autoimmune phenomena and of major infections requiring parental antibiotics. At a time when aggressive therapeutic strategies are always more frequently used in the management of CLL, the distinctive features of patients with long-lived stable disease should be prospectively identified at presentation.
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PMID:Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features. 1267 80

As part of an extensive multi-institutional DIANAIDS study focused on assessing the risk factors, natural history, diagnosis and follow-up of genital human papillomavirus (HPV) infections in HIV-infected women, the present communication reports a sub-cohort of 142 women (89 HIV+ and 48 HIV-), followed-up for a mean of 14.07 (+/-10.84) months to analyse the factors predicting the persistence and clearance of HPV infections (polymerase chain reaction [PCR] and sequencing) and cervical Papanicolaou (PAP) smear abnormalities, using both univariate (Kaplan-Meier) and multivariate (Cox) survival analysis. The appearance of new HPV infections during the follow-up was significantly more frequent in HIV-positive than in HIV-negative women, odds ratio (OR) 8.800 (95% confidence interval [CI]: 1.199-64.611), and also the clearance rate was significantly less frequent in HIV-positive than in HIV-negative women, 69.2% vs 22.8%, respectively (OR 0.330; 95% CI: 0.163-0.670). These two groups were also markedly different with respect to the clinical course of the cervical lesions, in the frequency of progressive disease (determined by PAP smear) was higher in HIV-positive group (12/89) than in HIV-negative women (2/52) (OR 3.506; 95% CI 0.816-15.055) (P = 0.055), in whom the disease regressed more frequently than in HIV-positive women (13.5% vs 7.9%) (OR 0.584; 95% CI 0.217-1.573). Using (1) HPV-positivity, (2) oncogenic HPV-type and (3) significant PAP smear abnormality at the end of follow-up as outcome measures, (1) was significantly (P < 0.001) predicted by the following variables in univariate analysis: age, mode of contraception, CD4 count, and HIV-positivity. The significant predictors of (2) were age and mode of contraception. The outcome measure (3) was significantly predicted by CD4 count, PAP smear abnormality and PCR status at entry. In the multivariate analysis, the significant independent predictive factors for HPV-positivity proved to be only the HIV status (P < 0.001), and PCR status at entry, p53 polymorphism at aa-72, oncogenic HPV type and significant PAP smear at entry remained independent predictors, with the significance level of P < 0.05. None of the significant predictors of oncogenic HPV type in univariate analysis retained their independent value in multivariate analysis. Oncogenic HPV type at entry proved to be an independent predictor of significant PAP smear (P < 0.05). The present results indicate that HIV-infected women, even on highly active antiretroviral therapy, demonstrate a more aggressive clinical course of cervical HPV infections, and fail to eradicate the disease more frequently than HIV-negative women. This persistence of HPV-positivity, oncogenic HPV type and significant PAP smear abnormality can be predicted by the results of PAP test and HPV typing in univariate analyses, and partly retain their independent predictive value also in multivariate analysis. Clearly, in addition to regular monitoring by PAP smear, HPV testing for the oncogenic HPV types seems to provide additional prognostic information in the management of cervical lesions in HIV-infected women.
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PMID:Factors predicting the persistence of genital human papillomavirus infections and PAP smear abnormality in HIV-positive and HIV-negative women during prospective follow-up. 1281 71

Current evidence suggests that the optimal vaccines for cancer should incorporate tumor-specific cytotoxic as well as helper epitopes. Wild-type sequence (wt) p53 peptides are attractive candidates for broadly applicable cancer vaccines, which could combine multiple tumor epitopes defined by CD8(+) CTLs, as well as CD4(+) T-helper cells. To test this possibility, we generated anti-p53 CD4(+) T cells from peripheral blood obtained from an HLA-DRB1*0401(+) donor by in vitro stimulation with dendritic cells and recombinant human p53 protein. We identified the wt p53(110-124) peptide as a naturally presented epitope. In a series of ex vivo experiments, performed in an autologous human system, we then demonstrated the ability of anti-wt p53(110-124) CD4(+) T cells to enhance the generation and antitumor functions of CD8(+) effector cells. The results demonstrate the crucial role of T helper-defined epitopes in shaping the immune response to multiepitope cancer vaccines targeting p53. This model of tumor-specific CD8(+) and CD4(+) T-cell interactions suggests that future vaccination strategies targeting tumor cells should incorporate helper and cytotoxic T cell-defined epitopes.
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PMID:P53(110-124)-specific human CD4+ T-helper cells enhance in vitro generation and antitumor function of tumor-reactive CD8+ T cells. 1283 58


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