TP53; tumor protein p53 (17p13.1)

Gene Summary

Gene:TP53; tumor protein p53
Aliases: P53, BCC7, LFS1, TRP53
Summary:This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons (PMIDs: 12032546, 20937277). [provided by RefSeq, Feb 2013]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:cellular tumor antigen p53
Updated:14 December, 2014


What does this gene/protein do?
Show (128)


What pathways are this gene/protein implicaed in?
- Apoptotic Signaling in Response to DNA Damage BIOCARTA
- ATM Signaling Pathway BIOCARTA
- BTG family proteins and cell cycle regulation BIOCARTA
- Cell Cycle BIOCARTA
- Cell Cycle BIOCARTA
- Chaperones modulate interferon Signaling Pathway BIOCARTA
- Double Stranded RNA Induced Gene Expression BIOCARTA
- Estrogen-responsive protein Efp controls cell cycle and breast tumors growth BIOCARTA
- Hypoxia and p53 in the Cardiovascular system BIOCARTA
- Overview of telomerase protein component gene hTert Transcriptional Regulation BIOCARTA
- p53 Signaling Pathway BIOCARTA
- RB Tumor Suppressor/Checkpoint Signaling in response to DNA damage BIOCARTA
- Regulation of cell cycle progression by Plk3 BIOCARTA
- Regulation of transcriptional activity by PML BIOCARTA
- Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility BIOCARTA
- Telomeres, Telomerase, Cellular Aging, and Immortality BIOCARTA
- Tumor Suppressor Arf Inhibits Ribosomal Biogenesis BIOCARTA
- Amyotrophic lateral sclerosis (ALS) KEGG
- Apoptosis KEGG
- Cell cycle KEGG
- Colorectal cancer KEGG
- Huntington's disease KEGG
- MAPK signaling pathway KEGG
- Wnt signaling pathway KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (27)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerTP53 mutations in Breast Cancer View Publications1442
Lung CancerTP53 mutations in Lung Cancer View Publications1198
LeukaemiaTP53 and Leukaemia View Publications737
Liver CancerTP53 and Liver Cancer View Publications633
Brain Tumours, ChildhoodTP53 and Brain Tumours View Publications566
Bladder CancerTP53 and Bladder Cancer View Publications489
Colorectal CancerTP53 and Colorectal Cancer View Publications473
Lung Cancer, Non-Small CellTP53 and Non-Small Cell Lung Cancer View Publications453
Li-Fraumeni syndromeLi-Fraumeni Syndrome
Li-Fraumeni syndrome is an autosomal-dominant condition which predisposes to a range of different types of cancer. Many members of Li-Fraumeni families have a germline mutation of the TP53 gene. Compared to the general population people who inherit a mutant TP53 allele have a 25-fold increase in the chance of developing cancer by 50 yrs of age.
View Publications372
Esophageal CancerTP53 and Esophageal Cancer View Publications343
Prostate CancerTP53 and Prostate Cancer View Publications340
Ovarian CancerTP53 and Ovarian Cancer View Publications301
Endometrial CancerTP53 Mutations in Endometrial Cancer View Publications214
Chronic Lymphocytic LeukemiaTP53 and Chronic Lymphocytic Leukemia View Publications208
Laryngeal CancerTP53 and Laryngeal Cancer View Publications124
MelanomaTP53 and Melanoma View Publications123
Pancreatic CancerTP53 and Pancreatic Cancer View Publications118
OsteosarcomaTP53 mutation in Osteosarcoma View Publications104
Childhood LeukaemiaTP53 and Childhood Leukemia View Publications87
Adrenocortical CancerTP53 and Adrenocortical Carcinoma View Publications76
RhabdomyosarcomaTP53 and Rhabdomyosarcoma View Publications64
NeuroblastomaP53 and Neuroblastoma View Publications31
Ewing's SarcomaTP53 Mutations and aberrant expression in a sub-set of Ewing's SarcomaPrognostic
TP53 mutations are found in between 5-20% of Ewing's Sarcomas (Li et al, 2010). However, studies have also shown the EWS-FLI1 fusion protein, found in most Ewing's sarcomas, interacts with p53 and p53 pathways.
View Publications31
MesotheliomaTP53 mutation in Mesothelioma View Publications27
Fallopian tube cancerTP53 and Fallopian Tube Cancer View Publications25
MesotheliomaTP53 Transfer to Mesothelioma Cells (Gene Therapy) Therapy View Publications10
Hairy Cell LeukemiaTP53 AND Hairy Cell Leukemia View Publications3

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: TP53 (cancer-related)

Maimaitili Y, Guzailinuer W, Wang X, et al.
[Detection of p53 gene deletion in Xinjiang patients with chronic lymphocytic leukemia by fluorescence in situ hybridization and its clinical significance].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2014; 31(4):499-503 [PubMed] Related Publications
OBJECTIVE: To investigate the presence of p53 gene deletion in Xinjiang patients with chronic lymphocytic leukemia and its clinical significance.
METHODS: Interphase fluorescence in situ hybridization (FISH) was used to detect the p53 gene deletion in 77 patients with CLL. Presence of the deletion and its association with clinical and laboratory features as well as prognostic factors were analyzed. Kaplan-Meier method was used to calculate survivals, and the results were compared using a Log-rank test.
RESULTS: p53 gene deletion was found in 10 (12.9%) of the patients but none from the control group (P<0.05). The deletion was found in 12.5% (4/32) of ethnic Hans and 13.3% (6/45) of ethnic Uyghurs (P>0.05). No significant different distribution of p53 gene deletion was found in regard to sex, age, ethnicity, peripheral blood cell count (except for Hb) or the levels of lactate dehydrogenase, β2-micro globulin and CD38 (P>0.05). The deletion rate was higher in the group with high expression of ZAP-70 and patients with advanced stage disease than that in the group of low expression and early-stage CLL (P<0.05). Among 20 patients who received fludarabine therapy, the overall remission rate for those with p53 gene deletion (20%) was lower than those without (75%) (P<0.05). With a median follow-up time of 39.0 (8.0-136.0) months, 11 cases had died (14.3%), among them, 7 cases died from CLL and related complications, and all of them were founded p53 gene deletion. In patients with p53 gene deletion, the progression-free survival (18 months) was shorter than those without the deletion (55 months) (P<0.05).
CONCLUSION: The p53 gene deletion has been found in more than 10% of patients with CLL, and the deletion rate did not significantly differ between ethnic Han and Uyghur patients. The deletion is associated with advanced stage of the disease. High-level ZAP-70 expression and the presence of p53 deletion are associated with shorter survival and poor response to fludarabine containing therapy. Therefore, drugs affecting the p53 signaling pathway should be avoided.

Related: FISH Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology Fludarabine

Xue W, Chen S, Yin H, et al.
CRISPR-mediated direct mutation of cancer genes in the mouse liver.
Nature. 2014; 514(7522):380-4 [PubMed] Article available free on PMC after 16/04/2015 Related Publications
The study of cancer genes in mouse models has traditionally relied on genetically-engineered strains made via transgenesis or gene targeting in embryonic stem cells. Here we describe a new method of cancer model generation using the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system in vivo in wild-type mice. We used hydrodynamic injection to deliver a CRISPR plasmid DNA expressing Cas9 and single guide RNAs (sgRNAs) to the liver that directly target the tumour suppressor genes Pten (ref. 5) and p53 (also known as TP53 and Trp53) (ref. 6), alone and in combination. CRISPR-mediated Pten mutation led to elevated Akt phosphorylation and lipid accumulation in hepatocytes, phenocopying the effects of deletion of the gene using Cre-LoxP technology. Simultaneous targeting of Pten and p53 induced liver tumours that mimicked those caused by Cre-loxP-mediated deletion of Pten and p53. DNA sequencing of liver and tumour tissue revealed insertion or deletion mutations of the tumour suppressor genes, including bi-allelic mutations of both Pten and p53 in tumours. Furthermore, co-injection of Cas9 plasmids harbouring sgRNAs targeting the β-catenin gene and a single-stranded DNA oligonucleotide donor carrying activating point mutations led to the generation of hepatocytes with nuclear localization of β-catenin. This study demonstrates the feasibility of direct mutation of tumour suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new avenue for rapid development of liver cancer models and functional genomics.

Related: Liver Cancer PTEN AKT1 CTNNB1 gene

Ali A, Shah AS, Ahmad A
Gain-of-function of mutant p53: mutant p53 enhances cancer progression by inhibiting KLF17 expression in invasive breast carcinoma cells.
Cancer Lett. 2014; 354(1):87-96 [PubMed] Related Publications
Kruppel-like-factor 17 (KLF17) is a negative regulator of metastasis and epithelial-mesenchymal-transition (EMT). However, its expression is downregulated in metastatic breast cancer that contains p53 mutations. Here, we show that mutant-p53 plays a key role to suppress KLF17 and thereby enhances cancer progression, which defines novel gain-of-function (GOF) of mutant-p53. Mutant-p53 interacts with KLF17 and antagonizes KLF17 mediated EMT genes transcription. Depletion of KLF17 promotes cell viability, decreases apoptosis and induces drug resistance in metastatic breast cancer cells. KLF17 suppresses cell migration and invasion by decreasing CD44, PAI-1 and Cyclin-D1 expressions. Taken together, our results show that KLF17 is important for the suppression of metastasis and could be a potential therapeutic target during chemotherapy.

Related: Apoptosis Breast Cancer Cancer Prevention and Risk Reduction BCL1 Gene (CCND1)

Lázaro-Ibáñez E, Sanz-Garcia A, Visakorpi T, et al.
Different gDNA content in the subpopulations of prostate cancer extracellular vesicles: apoptotic bodies, microvesicles, and exosomes.
Prostate. 2014; 74(14):1379-90 [PubMed] Related Publications
BACKGROUND: Extracellular vesicles (EVs) are cell-derived membrane vesicles. EVs contain several RNAs such as mRNA, microRNAs, and ncRNAs, but less is known of their genomic DNA (gDNA) content. It is also unknown whether the DNA cargo is randomly sorted or if it is systematically packed into specific EV subpopulations. The aim of this study was to analyze whether different prostate cancer (PCa) cell-derived EV subpopulations (apoptotic bodies, microvesicles, and exosomes) carry different gDNA fragments.
METHODS: EV subpopulations were isolated from three PCa cell lines (LNCaP, PC-3, and RC92a/hTERT) and the plasma of PCa patients and healthy donors, and characterized by transmission electron microscopy, nanoparticle tracking analysis and total protein content. gDNA fragments of different genes were detected by real time quantitative PCR and confirmed by DNA sequencing.
RESULTS: We report that the concentration of EVs was higher in the cancer patients than in the healthy controls. EV subpopulations differed from each other in terms of total protein and DNA content. Analysis of gDNA fragments of MLH1, PTEN, and TP53 genes from the PCa cell-derived EV subpopulations showed that different EVs carried different gDNA content, which could even harbor specific mutations. Altogether, these results suggest that both nucleic acids and proteins are selectively and cell-dependently packed into the EV subtypes.
CONCLUSIONS: EVs derived from PCa cell lines and human plasma samples contain double-stranded gDNA fragments which could be used to detect specific mutations, making EVs potential biomarkers for cancer diagnostics and prognostics.

Related: Apoptosis PTEN Prostate Cancer

Gorrini C
Discovery of a p53 variant that controls metastasis.
Proc Natl Acad Sci U S A. 2014; 111(32):11576-7 [PubMed] Article available free on PMC after 12/02/2015 Related Publications

Vladušić T, Hrašćan R, Krušlin B, et al.
Histological groups of human postpubertal testicular germ cell tumours harbour different genetic alterations.
Anticancer Res. 2014; 34(8):4005-12 [PubMed] Related Publications
BACKGROUND: Testicular germ cell tumours are the most common malignancies in young males. Molecular biology studies of these tumours are often contradictory. Two histological groups, seminoma and non-seminoma, differ both morphologically and in malignant behaviour. Although a common cytogenetic feature is seen, namely the amplification of the 12p chromosomal region, the development mechanisms of less aggressive seminomas and more aggressive non-seminomas are unknown.
MATERIALS AND METHODS: Occurrence of structural genetic alterations was analyzed in 18 seminomas and 22 non-seminomas for genes involved in the malignant tumour phenotype: cadherin 1, Type 1, E-cadherin (Epithelial), CDH1; adenomatous polyposis coli, APC; NME/NM23 nucleoside diphosphate kinase 1, NME1; tumour protein P53, TP53; cyclin-dependent kinase inhibitor 2A, CDKN2A; retinoblastoma 1, RB1; RAD51 recombinase, RAD51; mutS homolog 2, MSH2; MutL homolog 1, MLH1; breast cancer 1, early onset, BRCA1; BCL2-Associated X Protein, BAX; ATP-Binding Cassette, Sub-Family G (WHITE), Member 2, ABCG2. Genetic alterations, loss of heterozygosity and microsatellite instability, were analyzed using restriction fragment or microsatellite repeat length polymorphisms.
RESULTS: A difference in genetic alteration occurrence between seminomas and non-seminomas was observed.
CONCLUSION: Occurrence of genetic alterations correlates with clinical behaviour of these tumours and may indicate that such alterations could occur early in the development of seminomas and non-seminomas.

Related: Germ Cell Tumors Testicular Cancer

Senturk S, Yao Z, Camiolo M, et al.
p53Ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state.
Proc Natl Acad Sci U S A. 2014; 111(32):E3287-96 [PubMed] Article available free on PMC after 12/02/2015 Related Publications
Although much is known about the underlying mechanisms of p53 activity and regulation, the factors that influence the diversity and duration of p53 responses are not well understood. Here we describe a unique mode of p53 regulation involving alternative splicing of the TP53 gene. We found that the use of an alternative 3' splice site in intron 6 generates a unique p53 isoform, dubbed p53Ψ. At the molecular level, p53Ψ is unable to bind to DNA and does not transactivate canonical p53 target genes. However, like certain p53 gain-of-function mutants, p53Ψ attenuates the expression of E-cadherin, induces expression of markers of the epithelial-mesenchymal transition, and enhances the motility and invasive capacity of cells through a unique mechanism involving the regulation of cyclophilin D activity, a component of the mitochondrial inner pore permeability. Hence, we propose that p53Ψ encodes a separation-of-function isoform that, although lacking canonical p53 tumor suppressor/transcriptional activities, is able to induce a prometastatic program in a transcriptionally independent manner.

Related: Non-Small Cell Lung Cancer Lung Cancer Mitochondrial Mutations in Cancer

Davies MP, Barash O, Jeries R, et al.
Unique volatolomic signatures of TP53 and KRAS in lung cells.
Br J Cancer. 2014; 111(6):1213-21 [PubMed] Related Publications
BACKGROUND: Volatile organic compounds (VOCs) are potential biomarkers for cancer detection in breath, but it is unclear if they reflect specific mutations. To test this, we have compared human bronchial epithelial cell (HBEC) cell lines carrying the KRAS(V12) mutation, knockdown of TP53 or both with parental HBEC cells.
METHODS: VOC from headspace above cultured cells were collected by passive sampling and analysed by thermal desorption gas chromatography mass spectrometry (TD-GC-MS) or sensor array with discriminant factor analysis (DFA).
RESULTS: In TD-GC-MS analysis, individual compounds had limited ability to discriminate between cell lines, but by applying DFA analysis combinations of 20 VOCs successfully discriminated between all cell types (accuracies 80-100%, with leave-one-out cross validation). Sensor array detection DFA demonstrated the ability to discriminate samples based on their cell type for all comparisons with accuracies varying between 77% and 93%.
CONCLUSIONS: Our results demonstrate that minimal genetic changes in bronchial airway cells lead to detectable differences in levels of specific VOCs identified by TD-GC-MS or of patterns of VOCs identified by sensor array output. From the clinical aspect, these results suggest the possibility of breath analysis for detection of minimal genetic changes for earlier diagnosis or for genetic typing of lung cancers.

Related: Lung Cancer KRAS gene

Yamaguchi T, Ikehara S, Nakanishi H, Ikehara Y
A genetically engineered mouse model developing rapid progressive pancreatic ductal adenocarcinoma.
J Pathol. 2014; 234(2):228-38 [PubMed] Related Publications
The premalignant lesions of pancreatic cancer, pancreatic intraepithelial neoplasia (PanIN), have a high frequency of mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS), and genetic alterations in the retinoblastoma (Rb)-E2 factor (E2F) and transformed 3T3 cell double minute 2 (MDM2)-p53 pathways accelerate development of pancreatic ductal adenocarcinoma. The viral oncoprotein SV40 large T antigen (TAg) can inhibit the effects of the Rb family of molecules and of p53 on these pathways, and targeted expression of TAg in mouse pancreas is associated with the development of endocrine or acinar cell tumours. In this study, to determine whether the viral oncoprotein promotes pancreatic duct carcinogenesis initiated by oncogenic KRAS, we generated mice expressing temperature-sensitive SV40 large T antigen (tsTAg) on pancreatic epithelial cells in the presence or absence of Kras(G12D) . Mice with pancreas-specific tsTAg expression developed acinar cell dysplasia by 22 weeks without PanIN formation, while mice expressing both tsTAg and Kras(G12D) developed highly aggressive adenocarcinoma with a ductal cell phenotype within a short period, and died within 3 weeks. The tumours resembled human pancreatic ductal adenocarcinoma (PDAC) at the histological level, and oncogenic Kras and tsTAg synergistically activated E2f and Sre transcription in established PDAC cell lines. These results suggest that tsTAg synergistically promotes Kras(G12D) -associated PDAC formation, and our study identifies a new mouse model of PDAC that may allow a better understanding of the mechanism of carcinogenesis in pancreatic carcinoma, which shows a catastrophic clinical course.

Related: Cancer of the Pancreas Pancreatic Cancer

Milinkovic VP, Skender Gazibara MK, Manojlovic Gacic EM, et al.
The impact of TP53 and RAS mutations on cerebellar glioblastomas.
Exp Mol Pathol. 2014; 97(2):202-7 [PubMed] Related Publications
Cerebellar glioblastoma (cGBM) is a rare, inadequately characterized disease, without detailed information on its molecular basis. This is the first report analyzing both TP53 and RAS alterations in cGBM. TP53 mutations were detected in more than half of the samples from our cohort, mainly in hotspot codons. There were no activating mutations in hotspot codons 12/13 and 61 of KRAS and HRAS genes in cGBM samples but we detected alterations in other parts of exons 2 and 3 of these genes, including premature induction of STOP codon. This mutation was present in 3 out of 5 patients. High incidence of RAS mutations, as well as significantly longer survival of cGBM patients compared to those with supratentorial GBM suggest that cGBM may have different mechanisms of occurrence. Our results suggest that inactivation of TP53 and RAS may play an important role in the progression of cerebellar GBM.

Related: KRAS gene

Gupta R, Dong Y, Solomon PD, et al.
Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A.
Proc Natl Acad Sci U S A. 2014; 111(30):E3062-71 [PubMed] Article available free on PMC after 29/01/2015 Related Publications
Tumor suppressor p53 plays an important role in mediating growth inhibition upon telomere dysfunction. Here, we show that loss of the p53 target gene cyclin-dependent kinase inhibitor 1A (CDKN1A, also known as p21(WAF1/CIP1)) increases apoptosis induction following telomerase inhibition in a variety of cancer cell lines and mouse xenografts. This effect is highly specific to p21, as loss of other checkpoint proteins and CDK inhibitors did not affect apoptosis. In telomerase, inhibited cell loss of p21 leads to E2F1- and p53-mediated transcriptional activation of p53-upregulated modulator of apoptosis, resulting in increased apoptosis. Combined genetic or pharmacological inhibition of telomerase and p21 synergistically suppresses tumor growth. Furthermore, we demonstrate that simultaneous inhibition of telomerase and p21 also suppresses growth of tumors containing mutant p53 following pharmacological restoration of p53 activity. Collectively, our results establish that inactivation of p21 leads to increased apoptosis upon telomerase inhibition and thus identify a genetic vulnerability that can be exploited to treat many human cancers containing either wild-type or mutant p53.

Related: Apoptosis CDKN1A

Naryzhnyĭ SN, Ronzhina NL, Maĭnskova MA, et al.
[Development of barcode and proteome profiling of glioblastoma].
Biomed Khim. 2014 May-Jun; 60(3):308-21 [PubMed] Related Publications
High grade glioma (glioblastoma) is the most common brain tumor. Its malignancy makes it the fourth biggest cause of cancer death. In our experiments we used several glioblastoma cell lines generated in our laboratory to obtain proteomics information specific for this disease. This study starts our developing the complete 2DE map of glioblastoma proteins. 2DE separation with following imaging, immunochemistry, spot picking, and mass-spectrometry allowed us detecting and identifying more than 100 proteins. Several of them have prominent differences in their level between norm and cancer. Among them are alpha-enolase (ENOA_HUMAN), pyruvate kinase isozymes M1/M2 (KPYM_HUMAN), cofilin 1 (COF1_HUMAN), translationally-controlled tumor protein TCTP_HUMAN, annexin 1 (ANXA1_HUMAN), PCNA (PCNA_HUMAN), p53 (TP53_HUMAN) and others. Most interesting results were obtained with protein p53. In all glioblastoma cell lines, its level was dramatically up regulated and enriched by multiple additional isoforms. This distribution is well correlated with presence of these proteins inside of cells themselves. At this initial step we suggest the panel of specific brain tumor markers (signature) to help creating noninvasive techniques to diagnose disease. These preliminary data point to these proteins as promising markers of glioblastoma.

Related: PCNA: Proliferating cell nuclear antigen TPT1

Tabe Y, Kojima K
[Abnormal p53-HDM2 interaction in hematological malignancy].
Nihon Rinsho. 2014; 72(6):1042-6 [PubMed] Related Publications
The tumor suppressor protein p53 is a multifunctional transcription factor involved in the control of cell survival and death. p53 is inactivated by mutation of the p53 gene in approximately 50% of human cancers. While the rest (including hematological malignancies) encode wild-type p53, p53 is frequently inhibited by its negative regulator human double minute 2 (HDM2). HDM2 is a p53-specific E3 ubiquitin ligase. Therefore, there has been considerable interest in identifying compounds for disrupting the p53-HDM2 interaction. Small-molecule antagonist of HDM2, which binds HDM2 in the p53-binding pocket, negatively controls the activity of HDM2 and prevents p53 degradation. This stabilization of p53 results in its activation, leading to cell cycle arrest, growth inhibition, and apoptosis in wild type p53-haboring hematological malignant cells. Biology of p53-HDM2 interaction and anti-tumor effects of the HDM2 inhibitor in hematological malignant cells are described in this review.

Related: Haematological Malignancies & Realted Disorders MDM2 gene

Moorman AV
Does TP53 guard ALL genomes?
Blood. 2014; 124(2):160-1 [PubMed] Article available free on PMC after 29/01/2015 Related Publications

Du CX, Li SQ, Wang AH, Wang Y
Significance of combined detection of p53 and FHIT in cervical carcinoma diagnosis.
Eur J Gynaecol Oncol. 2014; 35(3):298-300 [PubMed] Related Publications
PURPOSE: To explore the significance of combined detection of p53 genes and fragile histidine triad (FHIT) genes in cervical carcinoma.
MATERIALS AND METHODS: Specimens taken from 161 cases invasive carcinoma, 23 cases carcinoma in situ or cervical intraepithelial neoplasia III (CIN III), 74 cases CIN I - II, 25 cases normal cervical tissue, and 32 cases tumor-adjacent tissues were processed by immunohistochemistry to determine the expression of p53 and FHIT genes. The results of the combined detection were compared for clinical diagnostic value of cervical carcinoma diagnosis.
RESULTS: The p53 gene, FHIT gene and the two genes combined examination of cervical carcinoma diagnostic sensitivity were: 65.8% (121/184), 66.3% (122/184), 90.2% (166/184), respectively. There were no significant differences between the p53 gene and the FHIT gene detected (p > 0.05). Combined detection of the two gene were more sensitivity than single detection, the difference was significant (p < 0.001). Although diagnosis specificity had dropped somewhat, no significant statistical appeared (chi2 = 0.022, p > 0.05).
CONCLUSION: Combined detection of p53 genes and FHIT genes can increase the sensitivity diagnosis and specificity diagnosis for early cervical carcinoma and precancerous lesions has a positive meaning.

Related: Cervical Cancer

Saito H, Ando S, Morishita N, et al.
A combined lymphokine-activated killer (LAK) cell immunotherapy and adenovirus-p53 gene therapy for head and neck squamous cell carcinoma.
Anticancer Res. 2014; 34(7):3365-70 [PubMed] Related Publications
BACKGROUND: The antitumor activity of lymphokine activated killer (LAK) cells immunotherapy is not always effective in all patients, especially when used alone. In this study, we investigated the in vitro antitumor activities of a combination of LAK immunotherapy and gene therapy employing an adenovirus carrying the p53 gene (Ad-p53) in human head and neck squamous cell carcinoma.
MATERIALS AND METHODS: The in vitro cytotoxicity of LAK cells was tested in H891 cells infected with or without Ad-p53, and the mRNA expression levels of natural killer group 2D ligands (UL16 binding protein (ULBP) 1 to 5) and tumor necrosis factor (TNF-α) in these cells were measured by real-time reverse transcription polymerase chain reaction.
RESULTS: Ad-p53 infection increased the cytotoxicity of LAK cells against H891 cells, and also increased the mRNA expression levels of the ULBPs in H891 cells and TNF-α in the LAK cells.
CONCLUSION: The antitumor activities of LAK cells in H891 cells were enhanced by Ad-p53.
CONCLUSION: The combinational therapy of LAK immunotherapy and Ad-p53 gene therapy may represent a new paradigm for the treatment of head and neck cancer.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Hypopharyngeal Cancer TNF

van der Ent W, Jochemsen AG, Teunisse AF, et al.
Ewing sarcoma inhibition by disruption of EWSR1-FLI1 transcriptional activity and reactivation of p53.
J Pathol. 2014; 233(4):415-24 [PubMed] Related Publications
Translocations involving ETS-transcription factors, most commonly leading to the EWSR1-FLI1 fusion protein, are the hallmark of Ewing sarcoma. Despite knowledge of this driving molecular event, an effective therapeutic strategy is lacking. To test potential treatment regimes, we established a novel Ewing sarcoma zebrafish engraftment model allowing time-effective, dynamic quantification of Ewing sarcoma progression and tumour burden in vivo, applicable for screening of single and combined compounds. In Ewing sarcoma the tumour-suppressor gene TP53 is commonly found to be wild-type, thus providing an attractive target for treatment. Here, we study TP53 wild-type (EW7, CADO-ES1 and TC32) and TP53-deleted (SK-N-MC) Ewing sarcoma cell lines to investigate the potentiating effect of p53 reactivation by Nutlin-3 on treatment with YK-4-279 to block transcriptional activity of EWSR1-FLI1 protein. Blocking EWSR1-FLI1 transcriptional activity reduced Ewing sarcoma tumour cell burden irrespective of TP53 status. We show that simultaneous YK-4-279 treatment with Nutlin-3 to stabilize p53 resulted in an additive inhibition of TP53 wild-type Ewing sarcoma cell burden, whilst not affecting TP53-deleted Ewing sarcoma cells. Improved inhibition of proliferation and migration by combinatorial treatment was confirmed in vivo by zebrafish engraftments. Mechanistically, both compounds together additively induced apoptosis of tumour cells in vivo by engaging distinct pathways. We propose reactivation of the p53 pathway in combination with complementary targeted therapy by EWSR1-FLI1 transcriptional activity disruption as a valuable strategy against p53 wild-type Ewing sarcoma.

Related: Bone Cancers Ewing's Sarcoma Signal Transduction

Derks S, Bass AJ
Mutational signatures in Helicobacter pylori-induced gastric cancer: lessons from new sequencing technologies.
Gastroenterology. 2014; 147(2):267-9 [PubMed] Related Publications

George TJ, O'Connell MJ
A new predictive molecular marker for cetuximab benefit in rectal cancer?
J Natl Cancer Inst. 2014; 106(7) [PubMed] Related Publications

Sclafani F, Gonzalez D, Cunningham D, et al.
TP53 mutational status and cetuximab benefit in rectal cancer: 5-year results of the EXPERT-C trial.
J Natl Cancer Inst. 2014; 106(7) [PubMed] Related Publications
In this updated analysis of the EXPERT-C trial we show that, in magnetic resonance imaging-defined, high-risk, locally advanced rectal cancer, adding cetuximab to a treatment strategy with neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX is not associated with a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) in both KRAS/BRAF wild-type and unselected patients. In a retrospective biomarker analysis, TP53 was not prognostic but emerged as an independent predictive biomarker for cetuximab benefit. After a median follow-up of 65.0 months, TP53 wild-type patients (n = 69) who received cetuximab had a statistically significant better PFS (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and OS (92.7% vs 67.5% at 5 years; HR = 0.16; 95% CI = 0.04 to 0.70; two-sided P = .02 by Cox regression) than TP53 wild-type patients who were treated in the control arm. An interaction between TP53 status and cetuximab effect was found (P < .05) and remained statistically significant after adjusting for statistically significant prognostic factors and KRAS.

Related: Cetuximab (Erbitux)

Kumar S, Liu L
No positive selection for G allele in a p53 response element in Europeans.
Cell. 2014; 157(7):1497-9 [PubMed] Related Publications

Sun H, Hattori N, Chien W, et al.
KPT-330 has antitumour activity against non-small cell lung cancer.
Br J Cancer. 2014; 111(2):281-91 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
BACKGROUND: We investigated the biologic and pharmacologic activities of a chromosome region maintenance 1 (CRM1) inhibitor against human non-small cell lung cancer (NSCLC) cells both in vitro and in vivo.
METHODS: The in vitro and in vivo effects of a novel CRM1 inhibitor (KPT-330) for a large number of anticancer parameters were evaluated using a large panel of 11 NSCLC cell lines containing different key driver mutations. Mice bearing human NSCLC xenografts were treated with KPT-330, and tumour growth was assessed.
RESULTS: KPT-330 inhibited proliferation and induced cell cycle arrest and apoptosis-related proteins in 11 NSCLC cells lines. Moreover, the combination of KPT-330 with cisplatin synergistically enhanced the cell kill of the NSCLC cells in vitro. Human NSCLC tumours growing in immunodeficient mice were markedly inhibited by KPT-330. Also, KPT-330 was effective even against NSCLC cells with a transforming mutation of either exon 20 of EGFR, TP53, phosphatase and tensin homologue, RAS or PIK3CA, suggesting the drug might be effective against a variety of lung cancers irrespective of their driver mutation.
CONCLUSIONS: Our results support clinical testing of KPT-330 as a novel therapeutic strategy for NSCLC.

Related: Apoptosis Non-Small Cell Lung Cancer Cisplatin Lung Cancer

Wang N, Zhu M, Wang X, et al.
Berberine-induced tumor suppressor p53 up-regulation gets involved in the regulatory network of MIR-23a in hepatocellular carcinoma.
Biochim Biophys Acta. 2014; 1839(9):849-57 [PubMed] Related Publications
AIM OF THE STUDY: To investigate the involvement of p53 in the regulatory network of microRNA-23a (miR-23a) in berberine-treated hepatocellular carcinoma (HCC) cells.
METHODS: The biogenesis of miR-23a upon berberine treatment was monitored by detecting the transcript expression of primary precursor, precursor and mature forms of miR-23a. Protein expression was detected with immunoblotting. The binding capacity between p53 and chromatin DNA was determined by chromatin immunoprecipitation. The role of miR-23a in mediating suppression of HCC by berberine was determined both in vitro and in vivo.
RESULTS: miR-23a was up-regulated upon berberine treatment in human HCC cells, and berberine could increase the expression of primary precursor, precursor and mature forms of miR-23a. The up-regulation of miR-23a by berberine is p53-dependent. Inhibition of p53 expression and activity could block the up-regulation of miR-23a induced by berberine. Furthermore, berberine-induced miR-23a expression may mediate the transcription activation of p53-related tumor suppressive genes p21 and GADD45α. Inhibition of miR-23a abolishes the binding of p53 onto chromatin and attenuates transcription activation of p21 and GADD45α. Target prediction and experimental validation demonstrate that berberine-induced miR-23a may target to Nek6 to suppress its expression. Berberine-induced G2/M cell cycle arrest in HCC was attenuated when miR-23a was inhibited. Berberine-induced cell death and in vivo tumor growth inhibition are attenuated upon inhibition of miR-23a.
CONCLUSION: Our study reveals that miR-23a may be involved in regulating the anti-HCC effect of berberine by mediating the regulation of p53.

Related: Liver Cancer

Qi C, Li S, Jia Y, Wang L
[Blueberry anthocyanins induce G2/M cell cycle arrest and apoptosis of oral cancer KB cells through down-regulation methylation of p53].
Yi Chuan. 2014; 36(6):566-73 [PubMed] Related Publications
Blueberries are an excellent source of dietary polyphenols such as anthocyanins and phenolic acids. In this study, we investigated the ability of anthocyanins from the wild blueberries of Inner Mongolia to suppress the growth of the oral cancer cell line KB. The blueberry anthocyanins were extracted with methanol-containing 0.1% (v/v) hydrochloric acid. Fourteen unique anthocyanins were identified using high-performance liquid chromatography-mass spectrometry (HPLC-MS). The anticancer bioactivity of the extracts on KB cells was analyzed using methylthiazolyl-tetrazolium (MTT), flow cytometry (FCM) and immunocytochemistry. It was shown that the blueberry anthocyanins suppressed the proliferation of KB cells in a dose-dependent manner, as well as induced G2/M cell cycle arrest and apoptosis of oral cancer KB cells. Immunocytochemistry analysis showed that the expression of caspase-9 and cytochrome c were obviously increased after the anthocyanins treatment. Western blot analysis also indicated that the expression of p53 was increased. Methylation-specific PCR (MSP) showed that the amount of unmethylated p53 increased, indicating that the anthocyanins can down-regulate the methylation of p53.

Related: Apoptosis Oral Cancer

Jiang YZ, Yu KD, Bao J, et al.
Favorable prognostic impact in loss of TP53 and PIK3CA mutations after neoadjuvant chemotherapy in breast cancer.
Cancer Res. 2014; 74(13):3399-407 [PubMed] Related Publications
We investigated the loss of somatic mutations in TP53 and PIK3CA in breast cancer tissue after neoadjuvant chemotherapy (NCT) and the clinical relevance of the observed mutation profiles. Samples were derived from three cohorts: Cohort 1 consisting of 206 patients undergoing NCT with matched pre- and postchemotherapy tumor tissues; Cohort 2 consisting of 158 additional patients undergoing NCT; and Cohort 3, consisting of 81 patients undergoing chemotherapy with prechemotherapy tumor tissues. In the first cohort, somatic mutations in TP53 or PIK3CA were identified in 24.8% of the pre-NCT tumor samples but in only 12.1% of the post-NCT tumor samples (P < 0.001). Patients with initial TP53 and PIK3CA mutations who became negative for the mutations after NCT had a higher Miller-Payne score (P = 0.008), improved disease-free survival, and improved overall survival than those with no change or the opposite change. The association of loss of mutations in TP53 and PIK3CA and improved survival was successfully validated in the second cohort. In addition, 28.4% of the tumors showed intratumoral heterogeneity of somatic mutations in TP53 or PIK3CA, whereas 71.6% were homogeneous, either with or without the mutations. Our data reveal the novel concept that chemotherapy may reduce mutation frequency in patients with breast cancer. Furthermore, the loss of somatic mutations in TP53 and PIK3CA may be translated to biomarkers for prognosis via further verification, which may optimize the choice of sequential therapy and improve patient survival.

Related: Breast Cancer Carboplatin Paclitaxel

Pietrantonio F, Biondani P, Perrone F, et al.
TP53 mutations in advanced colorectal cancer: the dark side of the moon.
Oncology. 2014; 86(5-6):289-94 [PubMed] Related Publications
BACKGROUND: Evidence for TP53 mutations as biomarker in colorectal cancer (CRC) is conflicting.
METHODS: We assessed TP53 mutations in 51 patients with advanced CRC enrolled into a phase II, randomised trial of first-line tegafur-uracil (UFT)/leucovorin (LV) plus irinotecan (n = 23) versus UFT/LV plus oxaliplatin (n = 28).
RESULTS: Non-functional TP53 mutations were found in 35% of patients. The response rate was not significantly different according to TP53 status. Progression-free and overall survival were longer in patients with TP53 mutations compared to those with wild-type TP53 (9 vs. 6.5 months, p = 0.0504, and 39.2 vs. 19.6 months, p = 0.0055, respectively). On multivariable analysis, TP53 mutation was independently associated with a decreased risk of death (hazard ratio 0.329, 95% CI 0.159-0.679; p = 0.0026). Treatment arm did not interact with TP53 in influencing outcomes.
CONCLUSION: TP53 was not predictive of benefit from first-line irinotecan- or oxaliplatin-based chemotherapy. TP53 mutations may possibly be associated with a more indolent course of CRC after the diagnosis of metastatic disease.

Related: Colorectal (Bowel) Cancer

Viros A, Sanchez-Laorden B, Pedersen M, et al.
Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.
Nature. 2014; 511(7510):478-82 [PubMed] Article available free on PMC after 24/01/2015 Related Publications
Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear. The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event. To investigate how UVR accelerates oncogenic BRAF-driven melanomagenesis, we used a BRAF(V600E) mouse model. In mice expressing BRAF(V600E) in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden. Here we show that sunscreen (UVA superior, UVB sun protection factor (SPF) 50) delayed the onset of UVR-driven melanoma, but only provided partial protection. The UVR-exposed tumours showed increased numbers of single nucleotide variants and we observed mutations (H39Y, S124F, R245C, R270C, C272G) in the Trp53 tumour suppressor in approximately 40% of cases. TP53 is an accepted UVR target in human non-melanoma skin cancer, but is not thought to have a major role in melanoma. However, we show that, in mice, mutant Trp53 accelerated BRAF(V600E)-driven melanomagenesis, and that TP53 mutations are linked to evidence of UVR-induced DNA damage in human melanoma. Thus, we provide mechanistic insight into epidemiological data linking UVR to acquired naevi in humans. Furthermore, we identify TP53/Trp53 as a UVR-target gene that cooperates with BRAF(V600E) to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis. Our study validates public health campaigns that promote sunscreen protection for individuals at risk of melanoma.

Related: Melanoma BRAF gene Skin Cancer

Antognelli C, Palumbo I, Aristei C, Talesa VN
Glyoxalase I inhibition induces apoptosis in irradiated MCF-7 cells via a novel mechanism involving Hsp27, p53 and NF-κB.
Br J Cancer. 2014; 111(2):395-406 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
BACKGROUND: Glyoxalase I (GI) is a cellular defence enzyme involved in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis, and MG-derived advanced glycation end products (AGEs). Argpyrimidine (AP), one of the major AGEs coming from MG modifications of proteins arginines, is a pro-apoptotic agent. Radiotherapy is an important modality widely used in cancer treatment. Exposure of cells to ionising radiation (IR) results in a number of complex biological responses, including apoptosis. The present study was aimed at investigating whether, and through which mechanism, GI was involved in IR-induced apoptosis.
METHODS: Apoptosis, by TUNEL assay, transcript and protein levels or enzymatic activity, by RT-PCR, western blot and spectrophotometric methods, respectively, were evaluated in irradiated MCF-7 breast cancer cells, also in experiments with appropriate inhibitors or using small interfering RNA.
RESULTS: Ionising radiation induced a dramatic reactive oxygen species (ROS)-mediated inhibition of GI, leading to AP-modified Hsp27 protein accumulation that, in a mechanism involving p53 and NF-κB, triggered an apoptotic mitochondrial pathway. Inhibition of GI occurred at both functional and transcriptional levels, the latter occurring via ERK1/2 MAPK and ERα modulation.
CONCLUSIONS: Glyoxalase I is involved in the IR-induced MCF-7 cell mitochondrial apoptotic pathway via a novel mechanism involving Hsp27, p53 and NF-κB.

Related: Apoptosis Breast Cancer

Zhu B, Ferry CH, Markell LK, et al.
The nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) promotes oncogene-induced cellular senescence through repression of endoplasmic reticulum stress.
J Biol Chem. 2014; 289(29):20102-19 [PubMed] Article available free on PMC after 18/07/2015 Related Publications
Endoplasmic reticulum (ER) stress and ER stress-associated unfolded protein response (UPR) can promote cancer cell survival, but it remains unclear whether they can influence oncogene-induced senescence. The present study examined the role of ER stress in senescence using oncogene-dependent models. Increased ER stress attenuated senescence in part by up-regulating phosphorylated protein kinase B (p-AKT) and decreasing phosphorylated extracellular signal-regulated kinase (p-ERK). A positive feed forward loop between p-AKT, ER stress, and UPR was discovered whereby a transient increase of ER stress caused reduced senescence and promotion of tumorigenesis. Decreased ER stress was further correlated with increased senescence in both mouse and human tumors. Interestingly, H-RAS-expressing Pparβ/δ null cells and tumors having increased cell proliferation exhibited enhanced ER stress, decreased cellular senescence, and/or enhanced tumorigenicity. Collectively, these results demonstrate a new role for ER stress and UPR that attenuates H-RAS-induced senescence and suggest that PPARβ/δ can repress this oncogene-induced ER stress to promote senescence in accordance with its role as a tumor modifier that suppresses carcinogenesis.

Related: PPARD AKT1 Signal Transduction Skin Cancer

Chan JY, Chen YC, Liu ST, et al.
Characterization of a new mouse p53 variant: loss-of-function and gain-of-function.
J Biomed Sci. 2014; 21:40 [PubMed] Article available free on PMC after 18/07/2015 Related Publications
BACKGROUND: p53 is a major tumor suppressor that is inactivated in over 50% of human cancer types through either mutation or inactivating interactions with viral or cellular proteins. The uncertainties around the link between p53 status, therapeutic response, and outcome in cancer suggest that additional factors may be involved. p53 isoforms that are generated via the alternative splicing pathway may be promising candidates for further investigation.
RESULT: In this study, we report one new p53 protein with two internally deleted regions, resulting in one deleted amino acid fragment (from amino acid residues 42 to 89) and one reading frame-shift region (from amino acid residues 90-120) compared to wild-type p53. The functional status of the new p53 protein, which has a defect in its proline-rich and N-terminal DNA-binding domains, was characterized as possessing an intact conformation, exhibiting no transactivation activity, exerting a dominant-negative effect and an interacting with a coactivator with an arginine methyltransferase activity.
CONCLUSION: Taken together, our findings provide valuable information about the structure and function of p53 for the regulation of transactivation activity and cellular protein-protein interactions. Furthermore, natural p53 isoforms will help us understand the functional roles of the p53 family and potential therapeutics for p53-dependent cancers.

Related: Apoptosis Cancer Prevention and Risk Reduction


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Cite this page: Cotterill SJ. TP53, Cancer Genetics Web: http://www.cancerindex.org/geneweb/TP53.htm Accessed: date

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