scholarly journals Tumor Eradication by Wild-type p53-specific Cytotoxic T Lymphocytes

1997 ◽  
Vol 186 (5) ◽  
pp. 695-704 ◽  
Author(s):  
Michel P.M. Vierboom ◽  
Hans W. Nijman ◽  
Rienk Offringa ◽  
Ellen I.H. van der Voort ◽  
Thorbald van Hall ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Tumor Cells ◽  
Cytotoxic T Lymphocytes ◽  
Normal Tissue ◽  
P53 Protein ◽  
P53 Gene ◽  
Wild Type ◽  
Wild Type P53 ◽  
Tumor Outgrowth ◽  
Tumor Eradication

The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies. The p53 protein is therefore an attractive target for immunotherapy. Cytotoxic T lymphocytes (CTLs) recognizing a murine wild-type p53 peptide, presented by the major histocompatibility complex class I molecule H-2Kb, were generated by immunizing p53 gene deficient (p53 −/−) C57BL/6 mice with syngeneic p53-overexpressing tumor cells. Adoptive transfer of these CTLs into tumor-bearing p53 +/+ nude mice caused complete and permanent tumor eradication. Importantly, this occurred in the absence of any demonstrable damage to normal tissue. When transferred into p53 +/+ immunocompetent C57BL/6 mice, the CTLs persisted for weeks in the absence of immunopathology and were capable of preventing tumor outgrowth. Wild-type p53-specific CTLs can apparently discriminate between p53-overexpressing tumor cells and normal tissue, indicating that widely expressed autologous molecules such as p53 can serve as a target for CTL-mediated immunotherapy of tumors.

scholarly journals Tolerance to p53 by A2.1-restricted Cytotoxic T Lymphocytes

1997 ◽  
Vol 185 (5) ◽  
pp. 833-842 ◽  
Author(s):  
Matthias Theobald ◽  
Judith Biggs ◽  
Javier Hernández ◽  
Joseph Lustgarten ◽  
Colleen Labadie ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Transgenic Mice ◽  
Cytotoxic T Lymphocytes ◽  
P53 Protein ◽  
High Avidity ◽  
Wild Type ◽  
Major Barrier ◽  
Cell Immunotherapy ◽  
Immunotherapy Of Cancer ◽  
Wild Type P53

Elevated levels of the p53 protein occur in ∼50% of human malignancies, which makes it an excellent target for a broad-spectrum T cell immunotherapy of cancer. A major barrier to the design of p53-specific immunotherapeutics and vaccines, however, is the possibility that T cells may be tolerant of antigens derived from wild-type p53 due to its low level of expression in normal thymus and lymphohemopoetic cells. The combination of p53 deficient (p53−/−) and p53+/+ HLA-A2.1/Kb transgenic mice was used as a model to explore the possibility that A2.1restricted cytotoxic T lymphocytes (CTL) are functionally tolerant of self peptides derived from the wild-type p53 tumor suppressor protein. A2.1-restricted CTL specific for a naturally processed p53 self-epitope spanning residues 187-197 were completely aborted in p53+/+ as opposed to p53−/− transgenic mice. In contrast, CTL specific for a second self-epitope spanning residues 261-269 of the murine p53 sequence were detected in both p53−/− and p53+/+ A2.1/Kb transgenic mice. However, the avidity of the CTL effectors obtained from p53+/+ mice was 10-fold lower than that obtained from p53−/− mice, again suggesting elimination of CTL with high avidity for the A2.1-peptide complex. The circumvention of functional tolerance of high avidity CTL may therefore be a necessary prerequisite for optimizing immunotherapy against A2.1-restricted wild-type p53 epitopes in humans.

scholarly journals The isolation of an RNA aptamer targeting to p53 protein with single amino acid mutation

2015 ◽  
Vol 112 (32) ◽  
pp. 10002-10007 ◽  
Author(s):  
Liang Chen ◽  
Farooq Rashid ◽  
Abdullah Shah ◽  
Hassaan M. Awan ◽  
Mingming Wu ◽  
...  
Keyword(s):  
P53 Protein ◽  
P53 Gene ◽  
P53 Mutation ◽  
Single Amino Acid ◽  
Human Lung Cancer ◽  
Rna Aptamer ◽  
Wild Type ◽  
Wild Type P53

p53, known as a tumor suppressor, is a DNA binding protein that regulates cell cycle, activates DNA repair proteins, and triggers apoptosis in multicellular animals. More than 50% of human cancers contain a mutation or deletion of the p53 gene, and p53R175 is one of the hot spots of p53 mutation. Nucleic acid aptamers are short single-stranded oligonucleotides that are able to bind various targets, and they are typically isolated from an experimental procedure called systematic evolution of ligand exponential enrichment (SELEX). Using a previously unidentified strategy of contrast screening with SELEX, we have isolated an RNA aptamer targeting p53R175H. This RNA aptamer (p53R175H-APT) has a significantly stronger affinity to p53R175H than to the wild-type p53 in both in vitro and in vivo assays. p53R175H-APT decreased the growth rate, weakened the migration capability, and triggered apoptosis in human lung cancer cells harboring p53R175H. Further analysis actually indicated that p53R175H-APT might partially rescue or correct the p53R175H to function more like the wild-type p53. In situ injections of p53R175H-APT to the tumor xenografts confirmed the effects of this RNA aptamer on p53R175H mutation in mice.

scholarly journals 2-[(4-Hydroxybenzyl) Amino] Phenol (HBAP) Restores the Mutated p53 to the Level Similar to That of Wild-Type p53 Protein and Inhibits Breast Cancer Growth in vivo to by Inducing Tumor Cells Apoptosis

2020 ◽  
Vol 8 ◽  
Author(s):  
Chenxi Xu ◽  
Jianjian Zhuang ◽  
Xiaobo Zhang
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Deep Sea ◽  
Breast Cancer Cells ◽  
P53 Protein ◽  
Mutant P53 ◽  
Wild Type ◽  
Amino Phenol ◽  
Wild Type P53

P53 is a transcriptional factor that plays important roles in apoptosis and is mutated in more than 50% of tumor cells. However, the restoration of mutated p53 to the level similar to wild-type p53 by a natural compound has not been explored intensively. In this study, the 2-[(4-hydroxybenzyl) amino] phenol (HBAP) compound, obtained from deep-sea virus-challenged thermophile Geobacillus sp. E263, interacted specifically with the mutated p53 protein. HBAP was able to induce apoptosis of p53-mutated breast cancer cells, but not normal breast cells and p53-unmutated breast cancer cells. HBAP activated the mutant p53 transcriptional activity by restoring the function of mutant p53 to that of wild-type p53. Further analysis indicated that HBAP bound only to the DNA binding domain of mutant p53 and that the interaction was dependent on the HBAP hydroxyl groups. In vivo data demonstrated that HBAP was toxicity-free and could suppress tumor growth by inducing tumor cell apoptosis. Therefore our findings revealed that recovering mutated p53 function to that of wild-type p53 caused by HBAP triggered cancer cell apoptosis and that metabolites from deep-sea virus-challenged thermophiles could be a promising source of anti-tumor drugs.

scholarly journals Wild-type p53 gene expression induces granulocytic differentiation of HL-60 cells

Blood ◽  
1994 ◽  
Vol 83 (8) ◽  
pp. 2230-2237 ◽  
Author(s):  
S Soddu ◽  
G Blandino ◽  
G Citro ◽  
R Scardigli ◽  
G Piaggio ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cellular Response ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
P53 Gene ◽  
Malignant Cell ◽  
Temperature Sensitive ◽  
Wild Type ◽  
Granulocytic Differentiation ◽  
Wild Type P53

Abstract Overexpression of wild-type p53 gene in malignant cell lines has been shown to inhibit cell proliferation in a number of cases. However, endogenous p53 protein seems to play little role in normal cell-cycle control as suggested by the normal development of p53 null mice, and by the low p53 protein levels expressed in most cell types. Recently, increased expression of endogenous p53 protein has been observed during the cellular response to DNA damage, as well as during differentiation of human hematopoietic cells. To study the role of the p53 gene in hematopoietic differentiation, we introduced the wild-type p53 gene or the temperature-sensitive p53(Val135) mutant into p53-deficient HL-60 promyelocytic leukemia cells. Morphological analysis, flow-cytometric determination of granulocytic or monocytic surface markers, and ability to reduce nitroblue tetrazolium (NBT) demonstrated that expression of exogenous wild-type p53 gene in HL-60 cells induces differentiation through the granulocytic pathway. Proliferation and cell-cycle analysis performed early after expression of wild-type p53 showed that induction of differentiation is not coupled with growth arrest, which suggests that p53 is involved in differentiation independently of its activity on the cell cycle.

scholarly journals Analysis of p53 mutants for transcriptional activity.

1991 ◽  
Vol 11 (12) ◽  
pp. 6067-6074 ◽  
Author(s):  
L Raycroft ◽  
J R Schmidt ◽  
K Yoas ◽  
M M Hao ◽  
G Lozano
Keyword(s):  
Transcription Factor ◽  
Fusion Protein ◽  
Fusion Proteins ◽  
P53 Protein ◽  
P53 Gene ◽  
Temperature Sensitive ◽  
Mutant P53 ◽  
Permissive Temperature ◽  
Wild Type ◽  
Wild Type P53

The wild-type p53 protein functions to suppress transformation, but numerous mutant p53 proteins are transformation competent. To examine the role of p53 as a transcription factor, we made fusion proteins containing human or mouse p53 sequences fused to the DNA binding domain of a known transcription factor, GAL4. Human and mouse wild-type p53/GAL4 specifically transactivated expression of a chloramphenicol acetyltransferase reporter in HeLa, CHO, and NIH 3T3 cells. Several mutant p53 proteins, including a mouse p53 mutant which is temperature sensitive for suppression, were also analyzed. A p53/GAL4 fusion protein with this mutation was also transcriptionally active only at the permissive temperature. Another mutant p53/GAL4 fusion protein analyzed mimics the mutation inherited in Li-Fraumeni patients. This fusion protein was as active as wild-type p53/GAL4 in our assay. Two human p53 mutants that arose from alterations of the p53 gene in colorectal carcinomas were 30- to 40-fold less effective at activating transcription than wild-type p53/GAL4 fusion proteins. Thus, functional wild-type p53/GAL4 fusion proteins activate transcription, while several transformation competent mutants do so poorly or not at all. Only one mutant p53/GAL4 fusion protein remained transcriptionally active.

scholarly journals Failure of wild-type p53 gene therapy in human cancer cells expressing a mutant p53 protein

Gene Therapy ◽  
1999 ◽  
Vol 6 (1) ◽  
pp. 22-33 ◽  
Author(s):  
A Vinyals ◽  
M A Peinado ◽  
M Gonzalez-Garrigues ◽  
M Monzó ◽  
R D Bonfil ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cancer Cells ◽  
Human Cancer ◽  
P53 Protein ◽  
P53 Gene ◽  
Mutant P53 ◽  
Wild Type ◽  
Human Cancer Cells ◽  
Wild Type P53

scholarly journals The correlation between the use of personal protective equipment and level wild-type p53 of dental technicians in Surabaya

2017 ◽  
Vol 50 (1) ◽  
pp. 19 ◽  
Author(s):  
Puspa Dila Rohmaniar ◽  
Titiek Berniyanti ◽  
Retno Pudji Rahayu
Keyword(s):  
Personal Protective Equipment ◽  
P53 Protein ◽  
Pearson Correlation ◽  
P53 Gene ◽  
Working Environment ◽  
Protective Equipment ◽  
Wild Type ◽  
Cross Sectional ◽  
Protein Levels ◽  
Wild Type P53

Background: Exposure of metals among dental technicians that come from the working environment can lead to the formation reactive oxygen species (ROS). ROS can cause mutations in the p53 gene (p53). The mutation is transversion mutation GuanineThymine. p53 mutations can lead to low expression of the wild-type p53 protein (p53). Wild-type p53 involved in many biological processes such as regulation of genes involved in cell cycle, cell growth after DNA damage, and apoptosis. However, exposure to metals among dental technicians can be prevented through the use of personal protective equipment (PPE) during work. Purpose: The purpose of this study was to analyze the correlation between the use of personal protective equipment to wild-type p53 protein levels among dental technicians in Surabaya. Method: This study was observational analytic with cross sectional approach. 40 samples were taken by random sampling. Data were retrieved through interviews and observations. Wild-type p53 was analyzed from saliva with indirect ELISA method. Analysis of data used Kolmogorov Smirnov normality test and a Pearson correlation test. Value significance was p<0.05 (95% confidence level). Result: There was a significant association between the use of personal protective equipment with wild-type p53 levels with p=0.002 Conclusion: The use PPE properly is positively correlated with the wild-type p53 protein levels of dental technicians in Surabaya.

scholarly journals Wild-type p53 gene expression induces granulocytic differentiation of HL-60 cells

Blood ◽  
1994 ◽  
Vol 83 (8) ◽  
pp. 2230-2237 ◽  
Author(s):  
S Soddu ◽  
G Blandino ◽  
G Citro ◽  
R Scardigli ◽  
G Piaggio ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cellular Response ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
P53 Gene ◽  
Malignant Cell ◽  
Temperature Sensitive ◽  
Wild Type ◽  
Granulocytic Differentiation ◽  
Wild Type P53

Overexpression of wild-type p53 gene in malignant cell lines has been shown to inhibit cell proliferation in a number of cases. However, endogenous p53 protein seems to play little role in normal cell-cycle control as suggested by the normal development of p53 null mice, and by the low p53 protein levels expressed in most cell types. Recently, increased expression of endogenous p53 protein has been observed during the cellular response to DNA damage, as well as during differentiation of human hematopoietic cells. To study the role of the p53 gene in hematopoietic differentiation, we introduced the wild-type p53 gene or the temperature-sensitive p53(Val135) mutant into p53-deficient HL-60 promyelocytic leukemia cells. Morphological analysis, flow-cytometric determination of granulocytic or monocytic surface markers, and ability to reduce nitroblue tetrazolium (NBT) demonstrated that expression of exogenous wild-type p53 gene in HL-60 cells induces differentiation through the granulocytic pathway. Proliferation and cell-cycle analysis performed early after expression of wild-type p53 showed that induction of differentiation is not coupled with growth arrest, which suggests that p53 is involved in differentiation independently of its activity on the cell cycle.

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