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TP53; tumor protein p53 (17p13.1)

Gene Summary

Gene:TP53; tumor protein p53
Aliases: P53, BCC7, LFS1, TRP53
Location:17p13.1
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
HPRD
Source:NCBI
Updated:17 January, 2015

Gene
Ontology:

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

Pathways:

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
- CTCF 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 (1990-2015)
Graph generated 17 January 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 17 January, 2015 using data from PubMed, MeSH and CancerIndex

Notable (30)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerTP53 mutations in Breast Cancer View Publications1453
Lung CancerTP53 mutations in Lung Cancer View Publications1208
LeukaemiaTP53 and Leukaemia View Publications745
Liver CancerTP53 and Liver Cancer View Publications637
Brain Tumours, ChildhoodTP53 and Brain Tumours View Publications572
Bladder CancerTP53 and Bladder Cancer View Publications489
Colorectal CancerTP53 and Colorectal Cancer View Publications479
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 Publications377
Esophageal CancerTP53 and Esophageal Cancer View Publications346
Prostate CancerTP53 and Prostate Cancer View Publications341
Ovarian CancerTP53 and Ovarian Cancer View Publications306
Endometrial CancerTP53 Mutations in Endometrial Cancer View Publications215
Chronic Lymphocytic LeukemiaTP53 and Chronic Lymphocytic Leukemia View Publications211
MelanomaTP53 and Melanoma View Publications125
Laryngeal CancerTP53 and Laryngeal Cancer View Publications124
Pancreatic CancerTP53 and Pancreatic Cancer View Publications121
OsteosarcomaTP53 mutation in Osteosarcoma View Publications105
Childhood LeukaemiaTP53 and Childhood Leukemia View Publications87
Adrenocortical CancerTP53 and Adrenocortical Carcinoma View Publications76
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 Publications27
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).

Related Links

Latest Publications: TP53 (cancer-related)

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.


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.

Related: Colorectal (Bowel) Cancer


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.

Related: Breast Cancer CGH BCL1 Gene (CCND1) PTPRC


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.

Related: Apoptosis Liver Cancer Signal Transduction


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.

Related: Liver Cancer MicroRNAs


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.

Related: Lung Cancer MDM2 gene


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.

Related: Cancer Prevention and Risk Reduction MDM2 gene MDM4 gene


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.

Related: Cancer Prevention and Risk Reduction MDM2 gene


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.

Related: Cancer Prevention and Risk Reduction MDM2 gene


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.

Related: Cancer Prevention and Risk Reduction


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.

Related: MicroRNAs


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.

Related: Cancer Prevention and Risk Reduction


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.

Related: Cancer Prevention and Risk Reduction


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.

Related: Cancer Prevention and Risk Reduction Signal Transduction


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.

Related: Li-Fraumeni Syndrome Cancer Prevention and Risk Reduction


Abdelmohsen K, Panda AC, Kang MJ, et al.
7SL RNA represses p53 translation by competing with HuR.
Nucleic Acids Res. 2014; 42(15):10099-111 [PubMed] Free Access to Full Article Related Publications
Noncoding RNAs (ncRNAs) and RNA-binding proteins are potent post-transcriptional regulators of gene expression. The ncRNA 7SL is upregulated in cancer cells, but its impact upon the phenotype of cancer cells is unknown. Here, we present evidence that 7SL forms a partial hybrid with the 3'-untranslated region (UTR) of TP53 mRNA, which encodes the tumor suppressor p53. The interaction of 7SL with TP53 mRNA reduced p53 translation, as determined by analyzing p53 expression levels, nascent p53 translation and TP53 mRNA association with polysomes. Silencing 7SL led to increased binding of HuR to TP53 mRNA, an interaction that led to the promotion of p53 translation and increased p53 abundance. We propose that the competition between 7SL and HuR for binding to TP53 3'UTR contributes to determining the magnitude of p53 translation, in turn affecting p53 levels and the growth-suppressive function of p53. Our findings suggest that targeting 7SL may be effective in the treatment of cancers with reduced p53 levels.

Related: Cancer Prevention and Risk Reduction


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 ZAP70 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


Viale A, Pettazzoni P, Lyssiotis CA, et al.
Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function.
Nature. 2014; 514(7524):628-32 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in western countries, with a median survival of 6 months and an extremely low percentage of long-term surviving patients. KRAS mutations are known to be a driver event of PDAC, but targeting mutant KRAS has proved challenging. Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases. Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling. Here we explore the role of mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras (Kras(G12D), herein KRas) in a p53(LoxP/WT) background. We demonstrate that a subpopulation of dormant tumour cells surviving oncogene ablation (surviving cells) and responsible for tumour relapse has features of cancer stem cells and relies on oxidative phosphorylation for survival. Transcriptomic and metabolic analyses of surviving cells reveal prominent expression of genes governing mitochondrial function, autophagy and lysosome activity, as well as a strong reliance on mitochondrial respiration and a decreased dependence on glycolysis for cellular energetics. Accordingly, surviving cells show high sensitivity to oxidative phosphorylation inhibitors, which can inhibit tumour recurrence. Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer.

Related: Mitochondrial Mutations in Cancer Cancer of the Pancreas Pancreatic Cancer Signal Transduction


Kong B, Wang Q, Fung E, et al.
p53 is required for cisplatin-induced processing of the mitochondrial fusion protein L-Opa1 that is mediated by the mitochondrial metallopeptidase Oma1 in gynecologic cancers.
J Biol Chem. 2014; 289(39):27134-45 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
Mitochondria are highly dynamic organelles, and mitochondrial fission is a crucial step of apoptosis. Although Oma1 is believed to be responsible for long form Opa1 (L-Opa1) processing during mitochondrial fragmentation, whether and how Oma1 is involved in L-Opa1 processing and participates in the regulation of chemoresistance is unknown. Chemosensitive and chemoresistant ovarian (OVCA) and cervical (CECA) cancer cells were treated with cisplatin (CDDP). Mitochondrial dynamics and protein contents were assessed by immunofluorescence and Western blot, respectively. The requirements of Oma1 and p53 for CDDP-induced L-Opa1 processing, mitochondrial fragmentation, and apoptosis were examined by siRNA or cDNA. CDDP induces L-Opa1 processing and mitochondrial fragmentation in chemosensitive but not in chemoresistant cells. CDDP induced Oma1 40-kDa form increases in OV2008 cells, not in C13* cells. Oma1 knockdown inhibited L-Opa1 processing, mitochondrial fragmentation, and apoptosis. Silencing p53 expression attenuated the effects of CDDP in Oma1 (40 kDa) increase, L-Opa1 processing, mitochondrial fragmentation, and apoptosis in chemosensitive OVCA cells, whereas reconstitution of p53 in p53 mutant or null chemoresistant OVCA cells induced Oma1 (40 kDa) increase, L-Opa1 processing, mitochondrial fragmentation, and apoptosis irrespective of the presence of CDDP. Prohibitin 1 (Phb1) dissociates from Opa1-Phb1 complex and binds phosphorylated p53 (serine 15) in response to CDDP in chemosensitive but not chemoresistant CECA cells. These findings demonstrate that (a) p53 and Oma1 mediate L-Opa1 processing, (b) mitochondrial fragmentation is involved in CDDP-induced apoptosis in OVCA and CECA cells, and (c) dysregulated mitochondrial dynamics may in part be involved in the pathophysiology of CDDP resistance.

Related: Apoptosis Cisplatin Ovarian Cancer Cervical Cancer


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


Gross AM, Orosco RK, Shen JP, et al.
Multi-tiered genomic analysis of head and neck cancer ties TP53 mutation to 3p loss.
Nat Genet. 2014; 46(9):939-43 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Head and neck squamous cell carcinoma (HNSCC) is characterized by aggressive behavior with a propensity for metastasis and recurrence. Here we report a comprehensive analysis of the molecular and clinical features of HNSCC that govern patient survival. We find that TP53 mutation is frequently accompanied by loss of chromosome 3p and that the combination of these events is associated with a surprising decrease in survival time (1.9 years versus >5 years for TP53 mutation alone). The TP53-3p interaction is specific to chromosome 3p and validates in HNSCC and pan-cancer cohorts. In human papillomavirus (HPV)-positive tumors, in which HPV inactivates TP53, 3p deletion is also common and is associated with poor outcomes. The TP53-3p event is modified by mir-548k expression, which decreases survival further, and is mutually exclusive with mutations affecting RAS signaling. Together, the identified markers underscore the molecular heterogeneity of HNSCC and enable a new multi-tiered classification of this disease.

Related: Chromosome 3 Head and Neck Cancers Head and Neck Cancers - Molecular Biology


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 CD24


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


Lin K, Farahani M, Yang Y, et al.
Loss of MIR15A and MIR16-1 at 13q14 is associated with increased TP53 mRNA, de-repression of BCL2 and adverse outcome in chronic lymphocytic leukaemia.
Br J Haematol. 2014; 167(3):346-55 [PubMed] Related Publications
This study was conducted to investigate the possibility that TP53 mRNA is variably expressed in chronic lymphocytic leukaemia (CLL) and that under-expression is associated with TP53 dysfunction and adverse outcome. Although TP53 mRNA levels did indeed vary among the 104 CLL samples examined, this variability resulted primarily from over-expression of TP53 mRNA in 18 samples, all of which lacked TP53 deletion/mutation. These patients had higher lymphocyte counts and shorter overall and treatment-free survival times compared to cases with low TP53 mRNA expression and no TP53 deletion/mutation. Furthermore, TP53 mRNA levels did not correlate with levels of TP53 protein or its transcriptional target CDKN1A. We speculated that the adverse outcome associated with TP53 mRNA over-expression might reflect variation in levels of MIR15A and MIR16-1, which are encoded on chromosome 13q14 and target TP53 and some oncogenes including BCL2. In keeping with our hypothesis, 13q14 copy number and levels of MIR15A/MIR16-1 correlated positively with one another but negatively with levels of TP53 mRNA and BCL2 mRNA. Our findings support a model in which loss of MIR15A/MIR16-1 at chromosome 13q14 results in adverse outcome due to de-repression of oncogenes such as BCL2, and up-regulation of TP53 mRNA as a bystander effect.

Related: Chromosome 13 Chromosome 17 CDKN1A BCL2 FISH Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology MicroRNAs


Shindiapina P, Brown JR, Danilov AV
A new hope: novel therapeutic approaches to treatment of chronic lymphocytic leukaemia with defects in TP53.
Br J Haematol. 2014; 167(2):149-61 [PubMed] Related Publications
Chronic lymphocytic leukaemia (CLL) is an indolent B-cell malignancy with heterogeneous outcomes. Chromosomal abnormalities in CLL are predictive of the natural disease course; del(11q) and del(17p) are recognized as high risk genetic lesions. Del(17p) is associated with an impaired function of TP53, a key tumour suppressor, and is particularly problematic. Such patients respond poorly to chemo-immunotherapy and have significantly shorter survival compared to patients with standard and low-risk cytogenetics. While TP53 pathway defects are rare at initial diagnosis, their frequency increases in relapsed CLL. Until very recently, this group of patients represented an unmet clinical need with few therapeutic options. However, the advent of targeted therapies has expanded the drug armamentarium and introduced new hope for these highly refractory patients. Agents that target B-cell receptor signalling, BH3-mimetics and others induce apoptosis of the neoplastic B-cells in a TP53-independent manner. Their use in the clinic is associated with remarkable activity in patients with del(17p). In this review we discuss the frequency and clinical significance of del(17p) and genetic mutations leading to disrupted TP53, the putative role of other TP53 homologues, and the results of key clinical trials involving both conventional chemotherapy and novel agents.

Related: Apoptosis Chromosome 17 Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology


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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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