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
Source:NCBIAccessed: 15 February, 2015


What does this gene/protein do?
Show (128)
Pathways:What pathways are this gene/protein implicaed in?
Show (25)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 15 February 2015 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 15 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (30)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerTP53 mutations in Breast Cancer View Publications1460
Lung CancerTP53 mutations in Lung Cancer View Publications1211
LeukaemiaTP53 and Leukaemia View Publications746
Liver CancerTP53 and Liver Cancer View Publications640
Brain Tumours, ChildhoodTP53 and Brain Tumours View Publications574
Bladder CancerTP53 and Bladder Cancer View Publications491
Colorectal CancerTP53 and Colorectal Cancer View Publications486
Lung Cancer, Non-Small CellTP53 and Non-Small Cell Lung Cancer View Publications456
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 Publications378
Esophageal CancerTP53 and Esophageal Cancer View Publications350
Prostate CancerTP53 and Prostate Cancer View Publications342
Ovarian CancerTP53 and Ovarian Cancer View Publications310
Endometrial CancerTP53 Mutations in Endometrial Cancer View Publications217
Chronic Lymphocytic LeukemiaTP53 and Chronic Lymphocytic Leukemia View Publications211
MelanomaTP53 and Melanoma View Publications126
Laryngeal CancerTP53 and Laryngeal Cancer View Publications124
Pancreatic CancerTP53 and Pancreatic Cancer View Publications122
OsteosarcomaTP53 mutation in Osteosarcoma View Publications110
Childhood LeukaemiaTP53 and Childhood Leukemia View Publications87
Adrenocortical CancerTP53 and Adrenocortical Carcinoma View Publications77
RhabdomyosarcomaTP53 and Rhabdomyosarcoma View Publications65
MedulloblastomaTP53 mutation in Medulloblastoma
In an ICGC deep sequencing study of 125 medulloblastoma tumour-normal pairs, (Jones DTW et al, 2012) reported TP53 somatic mutations in 5 (4%) of cases.
View Publications36
Lymphoma, Mantle-CellTP53 mutations in Mantle Cell Lymphoma
In a GWAS study Bea et al (2013) reported TP53 mutations in 28% (8/29) of MTC cases.
View Publications33
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 Publications28
Fallopian tube cancerTP53 and Fallopian Tube Cancer View Publications25
MesotheliomaTP53 Transfer to Mesothelioma Cells (Gene Therapy) Therapy View Publications10
MALT LymphomaTP53 and MALT Lymphoma 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).

Latest Publications: TP53 (cancer-related)

Ling X, Xu C, Fan C, et al.
FL118 induces p53-dependent senescence in colorectal cancer cells by promoting degradation of MdmX.
Cancer Res. 2014; 74(24):7487-97 [PubMed] Related Publications
Anticancer agent FL118 was recently identified in screening of small-molecule inhibitors of human survivin expression. Although FL118 is a camptothecin analogue, its antitumor potency is much superior to other FDA-approved camptothecin analogues (irinotecan and topotecan). The mechanism of action (MOA) underlying the antitumor effects of FL118 remains to be fully elucidated. Here, we report that FL118 activates tumor suppressor p53 as a novel MOA in p53 wild-type cancer cells. Our studies show that this MOA involves an induction of proteasomal degradation of MdmX, a critical negative regulator of p53, in a manner largely independent of ATM-dependent DNA damage signaling pathway but dependent on E3-competent Mdm2. FL118 inhibits p53 polyubiquitination and monoubiquitination by Mdm2-MdmX E3 complex in cells and in cell-free systems. In contrast, FL118 stimulates Mdm2-mediated MdmX ubiquitination. Coimmunoprecipitation revealed that FL118 slightly decreases Mdm2-p53 interactions and moderately increases Mdm2-MdmX interactions, suggesting a change of targeting specificity of Mdm2-MdmX E3 complex from p53 to MdmX, resulting in accelerated MdmX degradation. As a result, p53 ubiquitination by Mdm2-MdmX E3 complex is reduced, which in turn activates p53 signaling. Activation of the p53 pathway by FL118 induces p53-dependent senescence in colorectal cancer cells. However, in the absence of p53 or in the presence of MdmX overexpression, FL118 promotes p53-independent apoptosis. These two distinct cellular consequences collectively contribute to the potent effects of FL118 to inhibit clonogenic potential of colon cancer cells. This study identifies a potential application of FL118 as an MdmX inhibitor for targeted therapies.

Cooks T, Harris CC
p53 mutations and inflammation-associated cancer are linked through TNF signaling.
Mol Cell. 2014; 56(5):611-2 [PubMed] Related Publications
In this issue, Di Minin et al. (2014) link mutant p53 and chronic inflammation to tumorigenic progression via TNF signaling. Mutp53 interacts with the tumor suppressor DAB2IP in the cytoplasm, and induces a TNF-dependent transcriptional profile via NF-kB and JNK.

Meng X, Franklin DA, Dong J, Zhang Y
MDM2-p53 pathway in hepatocellular carcinoma.
Cancer Res. 2014; 74(24):7161-7 [PubMed] Related Publications
Abnormalities in the TP53 gene and overexpression of MDM2, a transcriptional target and negative regulator of p53, are commonly observed in cancers. The MDM2-p53 feedback loop plays an important role in tumor progression and thus, increased understanding of the pathway has the potential to improve clinical outcomes for cancer patients. Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the current treatment for HCC is less effective than those used against other cancers. We review the current studies of the MDM2-p53 pathway in cancer with a focus on HCC and specifically discuss the impact of p53 mutations along with other alterations of the MDM2-p53 feedback loop in HCC. We also discuss the potential diagnostic and prognostic applications of p53 and MDM2 in malignant tumors as well as therapeutic avenues that are being developed to target the MDM2-p53 pathway.

Di Minin G, Bellazzo A, Dal Ferro M, et al.
Mutant p53 reprograms TNF signaling in cancer cells through interaction with the tumor suppressor DAB2IP.
Mol Cell. 2014; 56(5):617-29 [PubMed] Related Publications
Inflammation is a significant factor in cancer development, and a molecular understanding of the parameters dictating the impact of inflammation on cancers could significantly improve treatment. The tumor suppressor p53 is frequently mutated in cancer, and p53 missense mutants (mutp53) can acquire oncogenic properties. We report that cancer cells with mutp53 respond to inflammatory cytokines increasing their invasive behavior. Notably, this action is coupled to expression of chemokines that can expose the tumor to host immunity, potentially affecting response to therapy. Mechanistically, mutp53 fuels NF-κB activation while it dampens activation of ASK1/JNK by TNFα, and this action depends on mutp53 binding and inhibiting the tumor suppressor DAB2IP in the cytoplasm. Interfering with such interaction reduced aggressiveness of cancer cells in xenografts. This interaction is an unexplored mechanism by which mutant p53 can influence tumor evolution, with implications for our understanding of the complex role of inflammation in cancer.

Dudgeon C, Chan C, Kang W, et al.
The evolution of thymic lymphomas in p53 knockout mice.
Genes Dev. 2014; 28(23):2613-20 [PubMed] Free Access to Full Article Related Publications
Germline deletion of the p53 gene in mice gives rise to spontaneous thymic (T-cell) lymphomas. In this study, the p53 knockout mouse was employed as a model to study the mutational evolution of tumorigenesis. The clonality of the T-cell repertoire from p53 knockout and wild-type thymic cells was analyzed at various ages employing TCRβ sequencing. These data demonstrate that p53 knockout thymic lymphomas arose in an oligoclonal fashion, with tumors evolving dominant clones over time. Exon sequencing of tumor DNA revealed that all of the independently derived oligoclonal mouse tumors had a deletion in the Pten gene prior to the formation of the TCRβ rearrangement, produced early in development. This was followed in each independent clone of the thymic lymphoma by the amplification or overexpression of cyclin Ds and Cdk6. Alterations in the expression of Ikaros were common and blocked further development of CD-4/CD-8 T cells. While the frequency of point mutations in the genome of these lymphomas was one per megabase, there were a tremendous number of copy number variations producing the tumors' driver mutations. The initial inherited loss of p53 functions appeared to delineate an order of genetic alterations selected for during the evolution of these thymic lymphomas.

Nason KS
Predicting response to neoadjuvant therapy in esophageal cancer with p53 genotyping: a fortune-teller's crystal ball or a viable prognostic tool?
J Thorac Cardiovasc Surg. 2014; 148(5):2286-7 [PubMed] Related Publications

Tang G, DiNardo C, Zhang L, et al.
MLL gene amplification in acute myeloid leukemia and myelodysplastic syndromes is associated with characteristic clinicopathological findings and TP53 gene mutation.
Hum Pathol. 2015; 46(1):65-73 [PubMed] Related Publications
MLL gene rearrangements are well-recognized aberrations in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In contrast, MLL gene amplification in AML/MDS remains poorly characterized. Here, we report a series of 21 patients with myeloid neoplasms associated with MLL gene amplification from 1 institution. This series included 13 men and 8 women, with a median age of 64 years. Eleven patients presented as AML with myelodysplasia-related changes, 6 as therapy-related AML, and 4 as therapy-related MDS. All patients had a highly complex karyotype, including frequent -5/del(5q), -18, and -17/del(17p) abnormalities; 16 patients were hypodiploid. TP53 mutations were detected in all 12 patients tested, and 3 patients showed TP53 mutation before MLL amplification. Morphologically, the leukemic cells frequently showed cytoplasmic vacuoles, bilobed nuclei, and were associated with background dyspoiesis. Immunophenotypically, 15 patients had a myeloid and 4 had myelomonocytic immunophenotype. Laboratory coagulopathies were common; 7 patients developed disseminated intravascular coagulopathy, and 3 died of intracranial bleeding. All patients were refractory to therapy; the median overall survival was 1 month, after MLL gene amplification was detected. We concluded that AML/MDS with MLL gene amplification is likely a subset of therapy-related AML/MDS or AML with myelodysplasia-related changes, associated with distinct clinicopathological features, frequent disseminated intravascular coagulopathy, a highly complex karyotype, TP53 deletion/mutation, and an aggressive clinical course.

Ashworth J, Bernard B, Reynolds S, et al.
Structure-based predictions broadly link transcription factor mutations to gene expression changes in cancers.
Nucleic Acids Res. 2014; 42(21):12973-83 [PubMed] Free Access to Full Article Related Publications
Thousands of unique mutations in transcription factors (TFs) arise in cancers, and the functional and biological roles of relatively few of these have been characterized. Here, we used structure-based methods developed specifically for DNA-binding proteins to systematically predict the consequences of mutations in several TFs that are frequently mutated in cancers. The explicit consideration of protein-DNA interactions was crucial to explain the roles and prevalence of mutations in TP53 and RUNX1 in cancers, and resulted in a higher specificity of detection for known p53-regulated genes among genetic associations between TP53 genotypes and genome-wide expression in The Cancer Genome Atlas, compared to existing methods of mutation assessment. Biophysical predictions also indicated that the relative prevalence of TP53 missense mutations in cancer is proportional to their thermodynamic impacts on protein stability and DNA binding, which is consistent with the selection for the loss of p53 transcriptional function in cancers. Structure and thermodynamics-based predictions of the impacts of missense mutations that focus on specific molecular functions may be increasingly useful for the precise and large-scale inference of aberrant molecular phenotypes in cancer and other complex diseases.

Morgado-Palacin L, Llanos S, Urbano-Cuadrado M, et al.
Non-genotoxic activation of p53 through the RPL11-dependent ribosomal stress pathway.
Carcinogenesis. 2014; 35(12):2822-30 [PubMed] Related Publications
Nucleolar disruption has recently emerged as a relevant means to activate p53 through inhibition of HDM2 by ribosome-free RPL11. Most drugs that induce nucleolar disruption also possess important genotoxic activity, which can have lasting mutagenic effects. Therefore, it is of interest to identify compounds that selectively produce nucleolar disruption in the absence of DNA damage. Here, we have performed a high-throughput screening to search for nucleolar disruptors. We have identified an acridine derivative (PubChem CID-765471) previously known for its capacity to activate p53 independently of DNA damage, although the molecular mechanism underlying p53 activation had remained uncharacterized. We report that CID-765471 produces nucleolar disruption by inhibiting ribosomal DNA transcription in a process that includes the selective degradation of the RPA194 subunit of RNA polymerase I. Following nucleolar disruption, CID-765471 activates p53 through the RPL11/HDM2 pathway in the absence of detectable DNA damage. In a secondary screening of compounds approved for medical use, we identify two additional acridine derivatives, aminacrine and ethacridine, that operate in a similar manner as CID-765471. These findings provide the basis for non-genotoxic chemotherapeutic approaches that selectively target the nucleolus.

Kawasumi M, Bradner JE, Tolliday N, et al.
Identification of ATR-Chk1 pathway inhibitors that selectively target p53-deficient cells without directly suppressing ATR catalytic activity.
Cancer Res. 2014; 74(24):7534-45 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Resistance to DNA-damaging chemotherapy is a barrier to effective treatment that appears to be augmented by p53 functional deficiency in many cancers. In p53-deficient cells in which the G1-S checkpoint is compromised, cell viability after DNA damage relies upon intact intra-S and G2-M checkpoints mediated by the ATR (ataxia telangiectasia and Rad3 related) and Chk1 kinases. Thus, a logical rationale to sensitize p53-deficient cancers to DNA-damaging chemotherapy is through the use of ATP-competitive inhibitors of ATR or Chk1. To discover small molecules that may act on uncharacterized components of the ATR pathway, we performed a phenotype-based screen of 9,195 compounds for their ability to inhibit hydroxyurea-induced phosphorylation of Ser345 on Chk1, known to be a critical ATR substrate. This effort led to the identification of four small-molecule compounds, three of which were derived from known bioactive library (anthothecol, dihydrocelastryl, and erysolin) and one of which was a novel synthetic compound termed MARPIN. These compounds all inhibited ATR-selective phosphorylation and sensitized p53-deficient cancer cells to DNA-damaging agents in vitro and in vivo. Notably, these compounds did not inhibit ATR catalytic activity in vitro, unlike typical ATP-competitive inhibitors, but acted in a mechanistically distinct manner to disable ATR-Chk1 function. Our results highlight a set of novel molecular probes to further elucidate druggable mechanisms to improve cancer therapeutic responses produced by DNA-damaging drugs.

Minchenko DO, Danilovskyi SV, Kryvdiuk IV, et al.
Acute L-glutamine deprivation affects the expression of TP53-related protein genes in U87 glioma cells.
Fiziol Zh. 2014; 60(4):11-21 [PubMed] Related Publications
We have studied the effect of acute L-glutamine deprivation on the expression oftumor protein 53 (TP53)-related genes such as TOPORS (topoisomerase I binding, arginine/serine-rich, E3 ubiquitin protein ligase), TP53BPI (TP53 bindingprotein 1), TP53TG1 (TP53 inducible gene 1), SESN1 (p53 regulatedPA26 nuclear protein), NME6 (NME/NM23 nucleoside diphosphate kinase 6), and ZMAT3 (zinc finger Matrin-type 3) in glioma cells with ERN1 knockdown. It was shown that blockade of ERN1 finction in U87 glioma cells is induced the expression of RYBP and SESN1 genes, but decreased the expression of TP53BP1, TP53TG1, TOPORS, NME6, genes. Moreover, the expression levels ofRYBPI SESN1, TP53BP1, and ZMAT3 genes is increased in control glioma cells by L-glutamine deprivation condition but blockade of ERN1 signaling enzyme function significantly enhances this effect on the expression all of these genes. At the same time, the ERN1 knockdown eliminates the response TP53TG1 and TOPORS genes to L-glutamine deprivation condition. Results of this investigation clearly demonstrate that the expression most of genes encoding TP53-related factors depends upon acute L-glutamine deprivation condition as well as upon ERN1, the major signaling system of the endoplasmic reticulum stress.

Fiorini C, Cordani M, Padroni C, et al.
Mutant p53 stimulates chemoresistance of pancreatic adenocarcinoma cells to gemcitabine.
Biochim Biophys Acta. 2015; 1853(1):89-100 [PubMed] Related Publications
Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths worldwide; PDAC is characterized by poor prognosis, resistance to conventional chemotherapy and high mortality rate. TP53 tumor suppressor gene is frequently mutated in PDAC, resulting in the accumulation of mutated protein with potential gain-of-function (GOF) activities, such as genomic instability, hyperproliferation and chemoresistance. The purpose of this study was to assess the relevance of the p53 status on the PDAC cells response to the standard drug gemcitabine. We also examined the potential therapeutic effect of p53-reactivating molecules to restore the mutant p53 function in GEM treated PDAC cells. We showed that gemcitabine stabilized mutant p53 protein in the nuclei and induced chemoresistance, concurrent with the mutant p53-dependent expression of Cdk1 and CCNB1 genes, resulting in a hyperproliferation effect. Despite the adverse activation of mutant p53 by gemcitabine, simultaneous treatment of PDAC cells with gemcitabine and p53-reactivating molecules (CP-31398 and RITA) reduced growth rate and induced apoptosis. This synergistic effect was observed in both wild-type and mutant p53 cell lines and was absent in p53-null cells. The combination drug treatment induced p53 phosphorylation on Ser15, apoptosis and autophagosome formation. Furthermore, pharmacological inhibition of autophagy further increased apoptosis stimulated by gemcitabine/CP-31398 treatment. Together, our results show that gemcitabine aberrantly stimulates mutant p53 activity in PDAC cells identifying key processes with potential for therapeutic targeting. Our data also support an anti-tumoral strategy based on inhibition of autophagy combined with p53 activation and standard chemotherapy for both wild-type and mutant p53 expressing PDACs.

Gao P, Li Q, Wang Z, et al.
[Significance of BCL6, MYC, P53 genes abnormalities for the prognosis of diffuse large B-cell lymphoma].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2014; 31(5):628-31 [PubMed] Related Publications
OBJECTIVE: To explore the influence of BCL6, MYC, P53 genes abnormalities can on the prognosis of diffuse large B-cell lymphoma (DLBCL), and to identify independent prognostic factors for DLBCL in order to facilitate clinical prognosis and selection of stratification treatment for the patients.
METHODS: Sixty five newly diagnosed DLBCL pathological specimens were collected from 2009 to 2012. Interphase fluorescence in situ hybridization technique (I-FISH) was used to detect the status of BCL6, MYC and P53 genes. Clinical factors were combined with immunohistochemical results for multiple-factor survival analysis.
RESULTS: The rates of BCL6 gene rearrangement, P53 gene deletion and MYC rearrangement were 21.5% (14/65), 35.4% (23/65) and 7.7% (5/65), respectively. BCL6 rearrangement group has obviously poorer overall survival (OS)(P< 0.05). COX proportional hazards model analysis showed that gender, BCL6 protein, BCL6 rearrangement, Ki67 index were prognosis factors independent of international prognostic index (IPI).
CONCLUSION: BCL6 can influence the prognosis of patients with DLBCL at gene and protein levels and both are independent prognostic factors for DLBCL.

Chung JH, Larsen AR, Chen E, Bunz F
A PTCH1 homolog transcriptionally activated by p53 suppresses Hedgehog signaling.
J Biol Chem. 2014; 289(47):33020-31 [PubMed] Article available free on PMC after 21/11/2015 Related Publications
The p53-mediated responses to DNA damage and the Hedgehog (Hh) signaling pathway are each recurrently dysregulated in many types of human cancer. Here we describe PTCH53, a p53 target gene that is homologous to the tumor suppressor gene PTCH1 and can function as a repressor of Hh pathway activation. PTCH53 (previously designated PTCHD4) was highly responsive to p53 in vitro and was among a small number of genes that were consistently expressed at reduced levels in diverse TP53 mutant cell lines and human tumors. Increased expression of PTCH53 inhibited canonical Hh signaling by the G protein-coupled receptor SMO. PTCH53 thus delineates a novel, inducible pathway by which p53 can repress tumorigenic Hh signals.

Buas MF, Levine DM, Makar KW, et al.
Integrative post-genome-wide association analysis of CDKN2A and TP53 SNPs and risk of esophageal adenocarcinoma.
Carcinogenesis. 2014; 35(12):2740-7 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Incidence of esophageal adenocarcinoma (EA) in Western countries has increased markedly in recent decades. Although several risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, less is known about the role of inherited genetic variation. Frequent somatic mutations in the tumor suppressor genes CDKN2A and TP53 were recently reported in EA tumors, while somatic alterations at 9p (CDKN2A) and 17p (TP53) have been implicated as predictors of progression from BE to EA. Motivated by these findings, we used data from a genome-wide association study of 2515 EA cases and 3207 controls to analyze 37 germline single nucleotide polymorphisms at the CDKN2A and TP53 loci. Three CDKN2A polymorphisms were nominally associated (P < 0.05) with reduced risk of EA: rs2518720 C>T [intronic, odds ratio 0.90, P = 0.0121, q = 0.3059], rs3088440 G>A (3'UTR, odds ratio 0.84, P = 0.0186, q = 0.3059), and rs4074785 C>T (intronic, odds ratio 0.85, P = 0.0248, q = 0.3059). None of the TP53 single nucleotide polymorphisms reached nominal significance. Two of the CDKN2A variants identified were also associated with reduced risk of progression from BE to EA, when assessed in a prospective cohort of 408 BE patients: rs2518720 (hazard ratio 0.57, P = 0.0095, q = 0.0285) and rs3088440 (hazard ratio 0.34, P = 0.0368, q = 0.0552). In vitro functional studies of rs3088440, a single nucleotide polymorphism located in the seed sequence of a predicted miR-663b binding site, suggested a mechanism whereby the G>A substitution may attenuate miR-663b-mediated repression of the CDKN2A transcript. This study provides the first evidence that germline variation at the CDKN2A locus may influence EA susceptibility.

Zhao Y, Ando K, Oki E, et al.
Aberrations of BUBR1 and TP53 gene mutually associated with chromosomal instability in human colorectal cancer.
Anticancer Res. 2014; 34(10):5421-7 [PubMed] Related Publications
BACKGROUND/AIM: Defects in mitotic checkpoint and p53-dependent pathways associate with chromosomal instability. In the present study, we investigated the interplay between BUBR1 and p53 and their association with genetic instability in colorectal cancer.
PATIENTS AND METHODS: 139 colorectal cases were examined for BUBR1, p53 and genetic instability indicators. BUBR1 expression was evaluated by immunohistochemistry and TP53 gene was directly sequenced. DNA ploidy was studied by laser scanning cytometry; MSI and TP53 loss of heterozygosity was also examined.
RESULTS: 64% of cases had high BUBR1 expression and were associated with the TP53 mutation. High BUBR1 expression and TP53 mutation associated with DNA aneuploidy and showed an inverse association with MSI. Cases with high BUBR1 expression and TP53 mutation had profound aneuploidy phenotypes and less frequent MSI compared to cases with one or neither aberration.
CONCLUSION: Our findings indicated an interplay between BUBR1 and p53 in colorectal cancer. Altered expression of both molecules was associated with chromosomal instability.

Perriaud L, Marcel V, Sagne C, et al.
Impact of G-quadruplex structures and intronic polymorphisms rs17878362 and rs1642785 on basal and ionizing radiation-induced expression of alternative p53 transcripts.
Carcinogenesis. 2014; 35(12):2706-15 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
G-quadruplex (G4) structures in intron 3 of the p53 pre-mRNA modulate intron 2 splicing, altering the balance between the fully spliced p53 transcript (FSp53, encoding full-length p53) and an incompletely spliced transcript retaining intron 2 (p53I2 encoding the N-terminally truncated Δ40p53 isoform). The nucleotides forming G4s overlap the polymorphism rs17878362 (A1 wild-type allele, A2 16-base pair insertion) which is in linkage disequilibrium with rs1642785 in intron 2 (c.74+38 G>C). Biophysical and biochemical analyses show rs17878362 A2 alleles form similar G4 structures as A1 alleles although their position is shifted with respect to the intron 2 splice acceptor site. In addition basal FSp53 and p53I2 levels showed allele specific differences in both p53-null cells transfected with reporter constructs or lymphoblastoid cell lines. The highest FSp53 and p53I2 levels were associated with combined rs1642785-GG/rs17878362-A1A1 alleles, whereas the presence of rs1642785-C with either rs17878362 allele was associated with lower p53 pre-mRNA, total TP53, FSp53 and p53I2 levels, due to the lower stability of transcripts containing rs1642785-C. Treatment of lymphoblastoid cell with the G4 binding ligands 360A or PhenDC3 or with ionizing radiation increased FSp53 levels only in cells with rs17878362 A1 alleles, suggesting that under this G4 configuration full splicing is favoured. These results demonstrate the complex effects of intronic TP53 polymorphisms on G4 formation and identify a new role for rs1642785 on mRNA splicing and stability, and thus on the differential expression of isoform-specific transcripts of the TP53 gene.

Neves RP, Raba K, Schmidt O, et al.
Genomic high-resolution profiling of single CKpos/CD45neg flow-sorting purified circulating tumor cells from patients with metastatic breast cancer.
Clin Chem. 2014; 60(10):1290-7 [PubMed] Related Publications
BACKGROUND: Circulating tumor cells (CTCs) are promising surrogate markers for systemic disease, and their molecular characterization might be relevant to guide more individualized cancer therapies. To enable fast and efficient purification of individual CTCs, we developed a work flow from CellSearch(TM) cartridges enabling high-resolution genomic profiling on the single-cell level.
METHODS: Single CTCs were sorted from 40 CellSearch samples from patients with metastatic breast cancer using a MoFlo XDP cell sorter. Genomes of sorted single cells were amplified using an adapter-linker PCR. Amplification products were analyzed by array-based comparative genomic hybridization, a gene-specific quantitative PCR (qPCR) assay for cyclin D1 (CCND1) locus amplification, and genomic sequencing to screen for mutations in exons 1, 9, and 20 of the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene and exons 5, 7, and 8 of the tumor protein p53 (TP53) gene.
RESULTS: One common flow-sorting protocol was appropriate for 90% of the analyzed CellSearch cartridges, and the detected CTC numbers correlated positively with those originally detected with the CellSearch system (R(2) = 0.9257). Whole genome amplification was successful in 72.9% of the sorted single CTCs. Over 95% of the cells displayed chromosomal aberrations typical for metastatic breast cancers, and amplifications at the CCND1 locus were validated by qPCR. Aberrant CTCs from 2 patients harbored mutations in exon 20 of the PIK3CA gene.
CONCLUSIONS: This work flow enabled effective CTC isolation and provided insights into genomic alterations of CTCs in metastatic breast cancer. This approach might facilitate further molecular characterization of rare CTCs to increase understanding of their biology and as a basis for their molecular screening in the clinical setting.

Sun J, Wang B, Liu Y, et al.
Transcription factor KLF9 suppresses the growth of hepatocellular carcinoma cells in vivo and positively regulates p53 expression.
Cancer Lett. 2014; 355(1):25-33 [PubMed] Related Publications
Krüppel-like factor 9 (KLF9) is known to be a tumor suppressor gene in colorectal tumors and glioblastoma; however, the functional status and significance of KLF9 in hepatocellular carcinoma (HCC) is unclear. We report here that KLF9 is downregulated in HCC tissues. Restoration of KLF9 significantly inhibited growth and caused apoptosis in SK-Hep1 and HepG2 cells. We found that KLF9 positively regulated p53 levels by directly binding to GC boxes within the proximal region of the p53 promoter. Moreover, in the presence of cycloheximide, KLF9 significantly increased p53 stability in HCC cells. Remarkably, ectopic expression of KLF9 was sufficient to delay the onset of tumors and to promote regression of the established tumors in vivo, suggesting that KLF9 plays a critical role in HCC development and that pharmacological or genetic activation of KLF9 may have potential in the treatment of HCC.

Xiao Z, Li CH, Chan SL, et al.
A small-molecule modulator of the tumor-suppressor miR34a inhibits the growth of hepatocellular carcinoma.
Cancer Res. 2014; 74(21):6236-47 [PubMed] Related Publications
Small molecules that restore the expression of growth-inhibitory microRNAs (miRNA) downregulated in tumors may have potential as anticancer agents. miR34a functions as a tumor suppressor and is downregulated or silenced commonly in a variety of human cancers, including hepatocellular carcinoma (HCC). In this study, we used an HCC cell-based miR34a luciferase reporter system to screen for miR34a modulators that could exert anticancer activity. One compound identified as a lead candidate, termed Rubone, was identified through its ability to specifically upregulate miR34a in HCC cells. Rubone activated miR34a expression in HCC cells with wild-type or mutated p53 but not in cells with p53 deletions. Notably, Rubone lacked growth-inhibitory effects on nontumorigenic human hepatocytes. In a mouse xenograft model of HCC, Rubone dramatically inhibited tumor growth, exhibiting stronger anti-HCC activity than sorafenib both in vitro and in vivo. Mechanistic investigations showed that Rubone decreased expression of cyclin D1, Bcl-2, and other miR34a target genes and that it enhanced the occupancy of p53 on the miR34a promoter. Taken together, our results offer a preclinical proof of concept for Rubone as a lead candidate for further investigation as a new class of HCC therapeutic based on restoration of miR34a tumor-suppressor function.

Gadepalli VS, Deb SP, Deb S, Rao RR
Lung cancer stem cells, p53 mutations and MDM2.
Subcell Biochem. 2014; 85:359-70 [PubMed] Related Publications
Over the past few decades, advances in cancer research have enabled us to understand the different mechanisms that contribute to the aberrant proliferation of normal cells into abnormal cells that result in tumors. In the pursuit to find cures, researchers have primarily focused on various molecular level changes that are unique to cancerous cells. In humans, about 50 % or more cancers have a mutated tumor suppressor p53 gene thereby resulting in accumulation of p53 protein and losing its function to activate the target genes that regulate cell cycle and apoptosis. Extensive research conducted in murine cancer models with activated p53, loss of p53, or p53 missense mutations have facilitated researchers to understand the role of this key protein. Despite the identification of numerous triggers that causes lung cancer specific cure still remain elusive. One of the primary reasons attributed to this is due to the fact that the tumor tissue is heterogeneous and contains numerous sub-populations of cells. Studies have shown that a specific sub-population of cells termed as cancer stem cells (CSCs) drive the recurrence of cancer in response to standard chemotherapy. These CSCs are mutated cells with core properties similar to those of adult stem cells. They reside in a microenvironment within the tumor tissue that supports their growth and make them less susceptible to drug treatment. These cells possess properties of symmetric self-renewal and migration thus driving tumor formation and metastasis. Therefore, research specifically targeting these cells has gained prominence towards developing new therapeutic agents against cancer. This chapter focuses on lung cancer stem cells, p53 mutations noted in these cells, and importance of MDM2 interactions. Further, research approaches for better understanding of molecular mechanisms that drive CSC function and developing appropriate therapies are discussed.

Zhang Q, Zeng SX, Lu H
Targeting p53-MDM2-MDMX loop for cancer therapy.
Subcell Biochem. 2014; 85:281-319 [PubMed] Related Publications
The tumor suppressor p53 plays a central role in anti-tumorigenesis and cancer therapy. It has been described as "the guardian of the genome", because it is essential for conserving genomic stability by preventing mutation, and its mutation and inactivation are highly related to all human cancers. Two important p53 regulators, MDM2 and MDMX, inactivate p53 by directly inhibiting its transcriptional activity and mediating its ubiquitination in a feedback fashion, as their genes are also the transcriptional targets of p53. On account of the importance of the p53-MDM2-MDMX loop in the initiation and development of wild type p53-containing tumors, intensive studies over the past decade have been aiming to identify small molecules or peptides that could specifically target individual protein molecules of this pathway for developing better anti-cancer therapeutics. In this chapter, we review the approaches for screening and discovering efficient and selective MDM2 inhibitors with emphasis on the most advanced synthetic small molecules that interfere with the p53-MDM2 interaction and are currently on Phase I clinical trials. Other therapeutically useful strategies targeting this loop, which potentially improve the prospects of cancer therapy and prevention, will also be discussed briefly.

Bohlman S, Manfredi JJ
p53-independent effects of Mdm2.
Subcell Biochem. 2014; 85:235-46 [PubMed] Related Publications
Mdm2 is best known as the primary negative regulator of p53, but a growing body of evidence suggests that Mdm2 also has a number of functions independent of its role in regulating p53. Although these functions are not yet well-characterized, they have been implicated in regulating of a number of cellular processes, including cell-cycle control, apoptosis, differentiation, genome stability, and transcription, among others. It appears that Mdm2 exerts these functions through a surprisingly wide variety of mechanisms. For example, it has been shown that Mdm2 can ubiquitinate alternative targets, can stimulate the activity of transcription factors, and can directly bind to mRNA to regulate its stability. Dysregulation of p53-independent functions could be responsible for the oncogenic properties of Mdm2 seen even in the absence of p53, and may explain why approximately 10 % of human tumors overexpress Mdm2 instead of inactivating p53 through other mechanisms. As the p53-independent functions of Mdm2 present novel targets for potential therapeutic interventions, fully characterizing these cellular and pathogenic roles of Mdm2 will be important in the study of tumor biology and the treatment of cancer.

Frum RA, Grossman SR
Mechanisms of mutant p53 stabilization in cancer.
Subcell Biochem. 2014; 85:187-97 [PubMed] Related Publications
p53 transactivates cell cycle inhibitory, apoptosis or senescence-related genes in response to DNA damage to protect the genetic integrity of the cell. Highlighting its critical tumor suppressor functions, p53 is mutated, lost, or functionally inactivated in nearly all cancers. When mutated within its core DNA binding domain, p53's normal instability is abrogated, and oncogenic gain-of-function properties are observed accompanied by massive accumulation of steady state mutant p53 protein levels relative to the low or undetectable steady state level of wild-type (WT) p53 in normal cells. Mutation of p53 may affect its stability through a combination of mutant p53's inherent biochemical and biophysical properties as well as pathways aberrantly activated in genetically damaged cells. The increased stability of mutant p53 proteins is key to its ability to accumulate to high levels and phenotypically exhibit "gain-of-function" properties. In this chapter we will address the multifaceted ways in which intrinsic mutant p53 properties intersect with emergent properties of cancer cells to yield the stable mutant p53 phenotype.

Tchelebi L, Ashamalla H, Graves PR
Mutant p53 and the response to chemotherapy and radiation.
Subcell Biochem. 2014; 85:133-59 [PubMed] Related Publications
In addition to playing roles in the genesis and progression of cancer, mutant p53 also appears to play a significant role in the response to cancer therapy. In response to chemotherapy and radiation, two mainstays of cancer treatment, most cancer cells harboring p53 mutations show a reduced sensitivity compared to cells lacking p53 or those with wild type p53. However, there are also many instances where mutant p53 has shown no effect or enhances cellular sensitivity to chemotherapy and radiation. Similar to the in vitro cellular studies, the majority of clinical studies show a correlation between the presence of mutant p53 in patient tumors and adverse outcomes following treatment with chemotherapy agents or radiation in comparison to tumors with wild-type p53. However, it still remains unclear whether the presence of mutant p53 in tumors can serve as a reliable prognostic factor and aid in treatment planning. Thus, as genomic analysis of patient tumors becomes more cost effective, the role of mutant p53 in tumor responses from cancer therapy ultimately needs to be addressed. This chapter will discuss current mechanisms of how p53 mutations affect cellular responses to chemotherapy and radiation and discuss patient outcomes based on p53 status.

Yeudall WA
p53 mutation in the genesis of metastasis.
Subcell Biochem. 2014; 85:105-17 [PubMed] Related Publications
Development of metastatic cancer is a complex series of events that includes genesis of tumor-related vascular and lymphatic systems, enhanced cellular motility, and the capacity to invade and survive at distant sites, as well as evasion of host defences. The wild-type p53 protein plays key roles in controlling these facets of tumor progression, and loss of normal p53 function can be sufficient to predispose tumor cells to gain metastatic properties. In contrast, dominant p53 mutants that have gained oncogenic functions can actively drive metastasis through a variety of mechanisms. This chapter aims to highlight these processes.

Santoro R, Strano S, Blandino G
Transcriptional regulation by mutant p53 and oncogenesis.
Subcell Biochem. 2014; 85:91-103 [PubMed] Related Publications
More than half of all human cancers carry p53 gene mutations whose resulting proteins are mostly full-length with a single amino acid change, abundantly present in cancer cells and unable to exert oncosuppressor activities. Frequently, mutant p53 proteins gain oncogenic functions through which they actively contribute to the establishment, the maintenance and the spreading of a given cancer cell. Intense research effort has been devoted to the deciphering of the molecular mechanisms underlying the gain of function of mutant p53 proteins. Here we mainly review the oncogenic transcriptional activity of mutant p53 proteins that mainly occurs through the aberrant cooperation with bona-fide transcription factors and leads to either aberrant up-regulation or down-regulation of selected target genes. Thus, mutant p53 proteins are critical components of oncogenic transcriptional networks that have a profound impact in human cancers.

Vaughan C, Pearsall I, Yeudall A, et al.
p53: its mutations and their impact on transcription.
Subcell Biochem. 2014; 85:71-90 [PubMed] Related Publications
p53 is a tumor suppressor protein whose key function is to maintain the integrity of the cell. Mutations in p53 have been found in up to 50 % of all human cancers and cause an increase in oncogenic phenotypes such as proliferation and tumorigenicity. Both wild-type and mutant p53 have been shown to transactivate their target genes, either through directly binding to DNA, or indirectly through protein-protein interactions. This review discusses possible mechanisms behind both wild-type and mutant p53-mediated transactivation and touches on the concept of addiction to mutant p53 of cancer cells and how that may be used for future therapies.

Girardini JE, Walerych D, Del Sal G
Cooperation of p53 mutations with other oncogenic alterations in cancer.
Subcell Biochem. 2014; 85:41-70 [PubMed] Related Publications
Following the initial findings suggesting a pro-oncogenic role for p53 point mutants, more than 30 years of research have unveiled the critical role exerted by these mutants in human cancer. A growing body of evidence, including mouse models and clinical data, has clearly demonstrated a connection between mutant p53 and the development of aggressive and metastatic tumors. Even if the molecular mechanisms underlying mutant p53 activities are still the object of intense scrutiny, it seems evident that full activation of its oncogenic role requires the functional interaction with other oncogenic alterations. p53 point mutants, with their pleiotropic effects, simultaneously activating several mechanisms of aggressiveness, are engaged in multiple cross-talk with a variety of other cancer-related processes, thus depicting a complex molecular landscape for the mutant p53 network. In this chapter revealing evidence illustrating different ways through which this cooperation may be achieved will be discussed. Considering the proposed role for mutant p53 as a driver of cancer aggressiveness, disarming mutant p53 function by uncoupling the cooperation with other oncogenic alterations, stands out as an exciting possibility for the development of novel anti-cancer therapies.

Merino D, Malkin D
p53 and hereditary cancer.
Subcell Biochem. 2014; 85:1-16 [PubMed] Related Publications
The roles of p53 as "guardian of the genome" are extensive, encompassing regulation of the cell cycle, DNA repair, apoptosis, cellular metabolism, and senescence - ultimately steering cells through a balance of death and proliferation. The majority of sporadic cancers exhibit loss of p53 activity due to mutations or deletions of TP53, and alterations in its signaling pathway. Germline TP53 mutations have been identified in a group of families exhibiting a rare but highly penetrant familial cancer syndrome, called the Li-Fraumeni syndrome (LFS). Between 60-80% of 'classic' LFS families carry mutant Trp53. The most frequent cancers observed are premenopausal breast cancer, bone and soft-tissue sarcomas, adrenal cortical carcinomas, and brain tumors. Penetrance is nearly 100% by age 70. Although TP53 is currently the only validated susceptibility locus recognized for LFS, recent studies have focused on the identification of genetic modifiers that may explain the wide phenotypic variability observed in LFS patients. Analyses of single nucleotide polymorphisms (SNPs), genome-wide copy number and telomere length have provided greater insight into the potential genetic modifiers of LFS. Moreover, the study of Trp53 mutant heterozygous mouse models has elucidated novel functions of p53, and offers insight into the mechanisms governing tumorigenesis in LFS. The key findings outlined in this chapter provide an overview of the molecular basis of LFS and the role of p53 in this unique heritable cancer syndrome.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. TP53, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 15 February, 2015     Cancer Genetics Web, Established 1999