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 from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]
TP53 is implicated in: - apoptotic process
- ATP binding
- B cell lineage commitment
- base-excision repair
- blood coagulation
- cell aging
- cell cycle
- cell cycle arrest
- cell cycle checkpoint
- cell differentiation
- cell proliferation
- cellular protein localization
- cellular response to drug
- cellular response to glucose starvation
- cellular response to hypoxia
- cellular response to ionizing radiation
- cellular response to UV
- central nervous system development
- chaperone binding
- chromatin assembly complex
- chromatin binding
- chromosome organization
- copper ion binding
- damaged DNA binding
- determination of adult lifespan
- DNA binding
- DNA damage response, signal transduction by p53 class mediator
- DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
- DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator
- DNA strand renaturation
- double-strand break repair
- endoplasmic reticulum
- enzyme binding
- ER overload response
- histone acetyltransferase binding
- histone deacetylase regulator activity
- identical protein binding
- in utero embryonic development
- induction of apoptosis
- intrinsic apoptotic signaling pathway
- intrinsic apoptotic signaling pathway by p53 class mediator
- intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
- metal ion binding
- mitotic cell cycle arrest
- mitotic cell cycle G1/S transition DNA damage checkpoint
- multicellular organism growth
- multicellular organismal development
- negative regulation of apoptotic process
- negative regulation of cell growth
- negative regulation of cell proliferation
- negative regulation of DNA replication
- negative regulation of fibroblast proliferation
- negative regulation of helicase activity
- negative regulation of neuroblast proliferation
- negative regulation of transcription from RNA polymerase II promoter
- negative regulation of transcription, DNA-dependent
- negative regulation of transforming growth factor beta receptor signaling pathway
- neuron apoptotic process
- nuclear body
- nuclear chromatin
- nuclear matrix
- nucleotide-excision repair
- oxidative stress-induced premature senescence
- p53 binding
- PML body
- positive regulation of apoptotic process
- positive regulation of cell aging
- positive regulation of cell cycle arrest
- positive regulation of histone deacetylation
- positive regulation of intrinsic apoptotic signaling pathway
- positive regulation of neuron apoptotic process
- positive regulation of peptidyl-tyrosine phosphorylation
- positive regulation of protein oligomerization
- positive regulation of reactive oxygen species metabolic process
- positive regulation of release of cytochrome c from mitochondria
- positive regulation of thymocyte apoptotic process
- positive regulation of transcription from RNA polymerase II promoter
- positive regulation of transcription, DNA-dependent
- protease binding
- protein binding
- protein complex
- protein complex assembly
- protein heterodimerization activity
- protein import into nucleus, translocation
- protein kinase binding
- protein localization
- protein N-terminus binding
- protein phosphatase 2A binding
- protein tetramerization
- Ras protein signal transduction
- regulation of apoptotic process
- regulation of mitochondrial membrane permeability
- regulation of transcription, DNA-dependent
- release of cytochrome c from mitochondria
- replication fork
- replicative senescence
- response to antibiotic
- response to DNA damage stimulus
- response to drug
- response to gamma radiation
- response to oxidative stress
- response to salt stress
- response to X-ray
- RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription
- RNA polymerase II transcription factor binding
- RNA polymerase II transcription regulatory region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription
- rRNA transcription
- sequence-specific DNA binding transcription factor activity
- T cell differentiation in thymus
- T cell lineage commitment
- T cell proliferation involved in immune response
- transcription factor binding
- transcription factor TFIID complex
- transcription regulatory region DNA binding
- transcription, DNA-dependent
- transforming growth factor beta receptor signaling pathway
- ubiquitin protein ligase binding
- virus-host interaction
- zinc ion binding
Data from Gene Ontology via CGAP [Hide]
What pathways are this gene/protein implicaed in? Show (25)
Li-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.
Nature Education Answers to questions such as How was it discovered? What are the persistent questions about its function? (Vogelstein, B., Sur, S. & Prives, C. (2010) p53 : The Most Frequently Altered Gene in Human Cancers. Nature Education 3(9):6)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
TP53 OMIM, Johns Hopkin University Referenced article focusing on the relationship between phenotype and genotype.
TP53 International Cancer Genome Consortium. Summary of gene and mutations by cancer type from ICGC
TP53 Cancer Genome Anatomy Project, NCI Gene Summary
TP53 COSMIC, Sanger Institute Somatic mutation information and related details
TP53 GEO Profiles, NCBI Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: TP53 (cancer-related)
Deben C, Van den Bossche J, Van Der Steen N, et al. Deep sequencing of the TP53 gene reveals a potential risk allele for non-small cell lung cancer and supports the negative prognostic value of TP53 variants. Tumour Biol. 2017; 39(2):1010428317694327 [PubMed] Related Publications
The TP53 gene remains the most frequently altered gene in human cancer, of which variants are associated with cancer risk, therapy resistance, and poor prognosis in several tumor types. To determine the true prognostic value of TP53 variants in non-small cell lung cancer, this study conducted further research, particularly focusing on subtype and tumor stage. Therefore, we determined the TP53 status of 97 non-small cell lung cancer adenocarcinoma patients using next generation deep sequencing technology and defined the prognostic value of frequently occurring single nucleotide polymorphisms and mutations in the TP53 gene. Inactivating TP53 mutations acted as a predictor for both worse overall and progression-free survival in stage II-IV patients and patients treated with DNA-damaging (neo)adjuvant therapy. In stage I tumors, the Pro-allele of the TP53 R72P polymorphism acted as a predictor for worse overall survival. In addition, we detected the rare R213R (rs1800372, minor allele frequency: 0.0054) polymorphism in 7.2% of the patients and are the first to show the significant association with TP53 mutations in non-small cell lung cancer adenocarcinoma patients (p = 0.003). In conclusion, Our findings show an important role for TP53 variants as negative predictors for the outcome of non-small cell lung cancer adenocarcinoma patients, especially for TP53 inactivating mutations in advanced stage tumors treated with DNA-damaging agents, and provide the first evidence of the R213R G-allele as possible risk factor for non-small cell lung cancer.
BACKGROUND: Genomic instability caused by mutation of the checkpoint molecule TP53 may endow cancer cells with the ability to undergo genomic evolution to survive stress and treatment. We attempted to gain insight into the potential contribution of ovarian cancer genomic instability resulted from TP53 mutation to the aberrant expression of multidrug resistance gene MDR1. METHODS: TP53 mutation status was assessed by performing nucleotide sequencing and immunohistochemistry. Ovarian cancer cell DNA ploidy was determined using Feulgen-stained smears or flow cytometry. DNA copy number was analyzed by performing fluorescence in situ hybridization (FISH). RESULTS: In addition to performing nucleotide sequencing for 5 cases of ovarian cancer, TP53 mutations were analyzed via immunohistochemical staining for P53. Both intensive P53 immunohistochemical staining and complete absence of signal were associated with the occurrence of TP53 mutations. HE staining and the quantification of DNA content indicated a significantly higher proportion of polyploidy and aneuploidy cells in the TP53 mutant group than in the wild-type group (p < 0.05). Moreover, in 161 epithelial ovarian cancer patients, multivariate logistic analysis identified late FIGO (International Federation of Gynecology and Obstetrics) stage, serous histotype, G3 grade and TP53 mutation as independent risk factors for ovarian cancer recurrence. In relapse patients, the proportion of chemoresistant cases in the TP53 wild-type group was significantly lower than in the mutant group (63.6% vs. 91.8%, p < 0.05). FISH results revealed a higher percentage of cells with >6 MDR1 copies and chromosome 7 amplication in the TP53 mutant group than in the wild-type group [11.7 ± 2.3% vs. 3.0 ± 0.7% and 2.1 ± 0.7% vs. 0.3 ± 0.05%, (p < 0.05), respectively]. And we observed a specific increase of MDR1 and chromosome 7 copy numbers in the TP53 mutant group upon disease regression (p < 0.01). CONCLUSIONS: TP53 mutation-associated genomic instability may promote chromosome 7 accumulation and MDR1 amplification during ovarian cancer chemoresistance and recurrence. Our findings lay the foundation for the development of promising chemotherapeutic approaches to treat aggressive and recurrent ovarian cancer.
Cabrita MA, Bose R, Vanzyl EJ, et al. The p53 protein induces stable miRNAs that have the potential to modify subsequent p53 responses. Gene. 2017; 608:86-94 [PubMed] Related Publications
The p53 tumour suppressor is a transcription factor that can increase the expression of mRNAs and microRNAs (miRNAs). HT29-tsp53 cells expressing a temperature sensitive variant of p53 have provided a useful model to rapidly and reversibly control p53 activity. In this model, the majority of p53-responsive mRNAs were upregulated rapidly but they were short-lived leading to rapid decay of the p53 response at the restrictive temperature. Here we used oligonucleotide microarrays and reverse transcriptase PCR to show that p53-induced miRNAs exhibited a distinct temporal pattern of expression. Whereas p53-induced miRNAs like miR-143-3p, miR-145-5p, miR-34a-5p and miR-139-5p increased as fast as mRNAs, they were extremely stable persisting long after p53 induced mRNAs and even their corresponding primary miRNAs had decayed to baseline levels. Three p53-induced mRNAs (MDM2, BTG2 and CDKN1A) are experimentally verified targets of one or more of these specific miRNAs so we hypothesized that the sustained expression of p53-induced miRNAs could be explained by a post-transcriptional feedback loop. Activation of consecutive p53 responses separated by a period of recovery led to the selective attenuation of a subset of p53 regulated mRNAs corresponding to those targeted by one or more of the p53-responsive miRNAs. Our results indicate that the long term expression of p53 responsive miRNAs leads to an excess of miRNAs during the second response and this likely prevents the induction of MDM2, BTG2 and CDKN1A mRNA and/or protein. These observations are likely to have important implications for daily cancer therapies that activate p53 in normal tissues and/or tumour cells.
Mechanical microenvironments, such as extracellular matrix stiffness and strain, have crucial roles in cancer progression. Cells sense their microenvironments with mechanosensing biomolecules, which is accompanied by the modulation of actin cytoskeleton structures, and the signals are subsequently transduced downstream as biochemical signals. The tumor suppressors p53 and retinoblastoma protein (Rb) are known to prevent cancer progression. The p53 and Rb signaling pathways are disrupted in many types of cancers. Here, we review recent findings about the roles of these tumor suppressors in the regulation of mechanosensing biomolecules and the actin cytoskeleton. We further discuss how dysfunction in the p53- and/or Rb-mediated mechanosignaling pathways is potentially involved in cancer progression. These pathways might provide good targets for developing anticancer therapies.
Subash-Babu P, Alshammari GM, Ignacimuthu S, Alshatwi AA Epoxy clerodane diterpene inhibits MCF-7 human breast cancer cell growth by regulating the expression of the functional apoptotic genes Cdkn2A, Rb1, mdm2 and p53. Biomed Pharmacother. 2017; 87:388-396 [PubMed] Related Publications
Systematic analyses of plants that are used in traditional medicine may lead to the discovery of novel cytotoxic secondary metabolites. Diterpene possesses multiple bioactivities; here, epoxy clerodane diterpene (ECD) was isolated from Tinospora cordifolia (Willd.) stem and shown potential antiproliferative effect in MCF-7 human breast cancer cells. The antiproliferative effect of ECD on MCF-7 cells was systematically analyzed by cell and nuclear morphology, alterations in oxidative stress, and the expression of tumor suppressor and mitochondria-mediated apoptosis-related genes. We found that the IC50 value of ECD was 3.2μM at 24h and 2.4μM at 48h. We observed that the cytotoxicity of ECD was specific to MCF-7 cells, whereas ECD was nontoxic to normal Vero and V79 cells. ECD significantly triggered intracellular ROS generation even from the lower doses of 0.6 and 1.2μM; and it is relative to higher dose of 2.4μM. Further, we used 0.6μM, 1.2μM and 2.4μM as experimental doses to analyze the relative dose-dependent effects. Nuclear staining revealed that cells treated with the 2.4μM dose exhibited characteristic apoptotic morphological changes and that 46% of the cells were apoptotic and 4% were necrotic after 48h. ECD significantly increased the expression of mitochondria-dependent apoptotic pathway-related genes after 48h; we observed significantly (p≤0.05) increased expression of CYP1A, GPX, GSK3β and TNF-α and downregulated expression of NF-κB. ECD also increased the expression of tumor suppressor genes such as Cdkn2A, Rb1 and p53. In addition, we observed that ECD treatment significantly (p≤0.001) upregulated the expression of apoptotic genes such as Bax, cas-3, cas-8, cas-9 and p21 and downregulated the expression of BCL-2, mdm2 and PCNA. In conclusion, ECD regulates the expression of Cdkn2A, p53 and mdm2 and induces apoptosis via the mitochondrial pathway in MCF-7 human breast cancer cells.
Merten L, Agaimy A, Moskalev EA, et al. Inactivating Mutations of RB1 and TP53 Correlate With Sarcomatous Histomorphology and Metastasis/Recurrence in Gastrointestinal Stromal Tumors. Am J Clin Pathol. 2016; 146(6):718-726 [PubMed] Related Publications
OBJECTIVES: Loss-of-function mutations in TP53 and CDKN2A have been found at varying frequencies in gastrointestinal stromal tumors (GISTs), while no mutations of RB1 have been reported to date. The aim of the current study was to determine the mutation frequency of TP53, RB1, and CDKN2A in GISTs. METHODS: A cohort of 83 primary untreated GISTs was analyzed for mutations in TP53, RB1, and CDKN2A by massive parallel sequencing. Tumors with mutations in TP53 and RB1 were analyzed by fluorescence in situ hybridization for the corresponding gene loci. RESULTS: Two GISTs harbored inactivating mutations in RB1, and two other GISTs displayed inactivating mutations in TP53 All four tumors were KIT mutant high-risk tumors with highly cellular sarcomatous histomorphology and variable combinations of plump spindle cells to epithelioid highly atypical cells and high mitotic activity. Three of these patients developed recurrent or metastatic disease, while the fourth patient showed tumor rupture intraoperatively. The combined overall frequency of TP53 and RB1 mutations was 13% considering high-risk or malignant GISTs. CONCLUSIONS: TP53 and RB1 mutations seem to be restricted to high-risk/malignant GISTs and occur at an equal although relatively low frequency.
Dasiram JD, Ganesan R, Kannan J, et al. Curcumin inhibits growth potential by G1 cell cycle arrest and induces apoptosis in p53-mutated COLO 320DM human colon adenocarcinoma cells. Biomed Pharmacother. 2017; 86:373-380 [PubMed] Related Publications
Curcumin, a natural polyphenolic compound and it is isolated from the rhizome of Curcuma longa, have been reported to possess anticancer effect against stage I and II colon cancer. However, the effect of curcumin on colon cancer at Dukes' type C metastatic stage III remains still unclear. In the present study, we have investigated the anticancer effects of curcumin on p53 mutated COLO 320DM human colon adenocarcinoma cells derived from Dukes' type C metastatic stage. The cellular viability and proliferation were assessed by trypan blue exclusion assay and MTT assay, respectively. The cytotoxicity effect was examined by lactate dehydrogenase (LDH) cytotoxicity assay. Apoptosis was analyzed by DNA fragmentation analysis, Hoechst and propidium iodide double fluorescent staining and confocal microscopy analysis. Cell cycle distribution was performed by flow cytometry analysis. Here we have observed that curcumin treatment significantly inhibited the cellular viability and proliferation potential of p53 mutated COLO 320DM cells in a dose- and time-dependent manner. In addition, curcumin treatment showed no cytotoxic effects to the COLO 320DM cells. DNA fragmentation analysis, Hoechst and propidium iodide double fluorescent staining and confocal microscopy analysis revealed that curcumin treatment induced apoptosis in COLO 320DM cells. Furthermore, curcumin caused cell cycle arrest at the G1 phase, decreased the cell population in the S phase and induced apoptosis in COLO 320DM colon adenocarcinoma cells. Together, these data suggest that curcumin exerts anticancer effects and induces apoptosis in p53 mutated COLO 320DM human colon adenocarcinoma cells derived from Dukes' type C metastatic stage.
Welch JS, Petti AA, Miller CA, et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med. 2016; 375(21):2023-2036 [PubMed] Related Publications
Background The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. Methods We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. Results Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. Conclusions Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).
Courtade-Saïdi M, Aziza J, d'Aure D, et al. Immunocytochemical staining for p53 and Ki-67 helps to characterise urothelial cells in urine cytology. Cytopathology. 2016; 27(6):456-464 [PubMed] Related Publications
OBJECTIVE: The presence of atypical cells in urine cytology is unsatisfactory for both cytologists and clinicians. The objective of this study was to test whether p53 and Ki-67 immunostaining could improve urothelial carcinoma (UC) detection on urinary cytology. METHODS: A total of 196 urine samples were analysed, 142 from the bladder, 41 from the upper tract and 13 from ileal bladder replacement. Cytology results were expressed as normal (N) (n = 81), atypia cannot exclude low-grade UC (ALG) (n = 25), suspicious for high-grade UC (SHG) (n = 39) and high-grade UC (HG) (n = 51). Actual diagnoses were confirmed by histopathological analysis, cystoscopic examination or follow-up for at least 1 year. Immunocytochemistry performed on CytoSpin(™) slides allowed the determination of the percentage of positive cells with p53 and Ki-67. RESULTS: The median percentage values [first to third quartile] of p53 and Ki-67 were 0 [0-5] and 0 [0-1] for N cytology, 5 [0-40] and 2 [1-10] for ALG, 10 [0-30] and 6 [3-25] for SHG, and 30 [10-80] and 20 [10-30] for HG, respectively. Statistically higher values were observed for both tests (P < 0.001) in positive cytologies (ALG, SHG and HG). The optimal cut-offs were 5% for p53 and 3% for Ki-67. The sensitivity and specificity for the detection of all UC were 86.4% and 76.7% for cytology alone, 81.3% and 93.2% for cytology and p53, 75.7% and 88% for cytology and Ki-67, and 68.9% and 97.5% for cytology, p53 and Ki-67, respectively. CONCLUSION: Using p53 and/or Ki-67 in addition to cytology increases the specificity without penalising the sensitivity.
Yao J, Huang A, Zheng X, et al. 53BP1 loss induces chemoresistance of colorectal cancer cells to 5-fluorouracil by inhibiting the ATM-CHK2-P53 pathway. J Cancer Res Clin Oncol. 2017; 143(3):419-431 [PubMed] Related Publications
PURPOSE: Loss of P53 binding protein 1 (53BP1) is considered a poor prognostic factor for colorectal cancer. However, its effect on chemosensitivity of colorectal cancer to 5-fluorouracil (5-FU) remains elusive. This study aimed to examine the association of 53BP1 expression with chemosensitivity of colorectal cancer cells to 5-FU. METHODS: Immunohistochemistry was performed on 30 metastatic colorectal cancer samples to assess the associations of 53BP1 levels with clinical therapeutic effects. In vitro, IC50 values for 5-FU and 53BP1 levels were determined by MTT assay and Western blot in 5 colorectal cancer cell lines. Then, 53BP1 was silenced in HCT116 and HT29 cells, and cell proliferation, apoptosis and cell cycle distribution were evaluated. Relative protein levels of ATM-CHK2-P53 pathway effectors and Bcl-2 family members were measured by Western blot. Finally, the effects of 53BP1 knockdown on tumor growth and 5-FU chemoresistance were investigated in vivo. RESULTS: 53BP1 expression was closely related to time to progression (TTP) after first-line chemotherapy. Namely, 53BP1 downregulation resulted in reduced TTP. In addition, 53BP1 silencing increased proliferation, inhibited apoptosis and induced S phase arrest in HCT116 and HT29 cells after 5-FU treatment. Moreover, 53BP1 knockdown also reduced the protein levels of ATM-CHK2-P53 apoptotic pathway effectors, caspase9 and caspase3, while increasing Bcl-2 expression. In vivo, 53BP1 silencing accelerated tumor proliferation in nude mice and enhanced resistance to 5-FU. CONCLUSIONS: These findings confirmed that 53BP1 loss might be a negative factor for chemotherapy efficacy, promoting cell proliferation and inhibiting apoptosis by suppressing ATM-CHK2-P53 signaling, and finally inducing 5-FU resistance.
Tian X, Dai S, Sun J, et al. Inhibition of MDM2 Re-Sensitizes Rapamycin Resistant Renal Cancer Cells via the Activation of p53. Cell Physiol Biochem. 2016; 39(5):2088-2098 [PubMed] Related Publications
BACKGROUND/AIMS: Rapamycin is a potential anti-cancer agent, which modulates the activity of mTOR, a key regulator of cell growth and proliferation. However, several types of cancer cells are resistant to the anti-proliferative effects of rapamycin. In this study, we report a MDM2/p53-mediated rapamycin resistance in human renal cancer cells. METHODS: Trypan blue exclusion tests were used to determine the cell viability. Changes in mRNA and protein expression were measured using real-time PCR and western blot, respectively. Xenograft models were established to evaluate the in vivo effects of rapamycin combined with a MDM2 inhibitor. RESULTS: Rapamycin treatment suppresses the expression of MDM2 and exogenous overexpression of MDM2 in A498 cells contributes to rapamycin resistance. By establishing a rapamycin resistant cell line, we observed that MDM2 was significantly upregulated in rapamycin resistant cells than that in rapamycin sensitive cells. Importantly, the rapamycin resistant cells demonstrated attenuated accumulation of p53 in the nucleus in response to rapamycin treatment. Moreover, the inhibition of MDM2 by siMDM2 sensitizes A498 cells to rapamycin through the activation of p53. In both in vitro and in vivo models, the combination of rapamycin with the MDM2 inhibitor, MI-319, demonstrated a synergistic inhibitory effect on rapamycin resistant cells. CONCLUSION: Our study reports a novel mechanism for rapamycin resistance in human renal cancer and provides a new perspective for the development of anti-cancer drugs.
Leekha A, Gurjar BS, Tyagi A, et al. Vitamin C in synergism with cisplatin induces cell death in cervical cancer cells through altered redox cycling and p53 upregulation. J Cancer Res Clin Oncol. 2016; 142(12):2503-2514 [PubMed] Related Publications
PURPOSE: Cervical cancer is the second most prevalent cancer in women worldwide. Survival of patients has been improved by cisplatin-based chemotherapy, but its effectiveness is limited due to its adverse effects on many tissues, especially nephrotoxicity. To optimize the efficacy of CDDP, we propose a combination therapy using natural products with minimal side effects. Vitamin C being a natural antioxidant is capable of selectively targeting cancer cells at pharmacological concentrations. Vitamin C synergistically enhances the activity of chemotherapeutic agents without increasing toxicity to normal cells. Therefore, we exploited co-therapy with cisplatin and vitamin C to kill cervical cancer cells. METHODS: We elucidated the role of CDDP and VC on cervical cancer cell line (SiHa) by using cell growth assays, DNA fragmentation analysis, comet assay, in vitro morphological assessment of apoptosis (AO/EB and DAPI staining), ROS analysis by DCFDA, flow cytometry, biochemical assays (GST, GSH, NO, catalase, TPA) and Western blotting. RESULTS: Our results clearly demonstrated that CDDP and VC treatment exhibited ameliorative effect on induction of cell death by p53 overexpression and generation of hydrogen peroxide in SiHa cells, thereby reducing the dosage of CDDP required to induce cell death in cancer cells. CONCLUSIONS: These studies provide novel approaches to combat cisplatin resistance in cervical cancer.
Gorjala P, Cairncross JG, Gary RK p53-dependent up-regulation of CDKN1A and down-regulation of CCNE2 in response to beryllium. Cell Prolif. 2016; 49(6):698-709 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
OBJECTIVES: Beryllium salts (here, beryllium sulphate) can produce a cytostatic effect in some cell types. The basis for this effect may include increased expression of proliferation inhibitors, reduced expression of proliferation promoters, or both. This study sought to determine the role of p53, the tumour-suppressing transcription factor, in mediating beryllium-induced cytostasis. MATERIALS AND METHODS: Human A172 glioma cells express wild-type TP53 gene. Activity of p53 was experimentally manipulated using siRNA and related approaches. Key elements of the beryllium-response were compared in normal and p53-knockdown A172 cells using RT-PCR and Western blotting. RESULTS: In A172 cells, 10 μm BeSO4 caused 300% increase in CDKN1A (cyclin-dependent kinase inhibitor p21) mRNA and 90% reduction of CCNE2 (cyclin E2) mRNA. The increased p21 mRNA and reduced cyclin E2 mRNA were each dependent on presence of functional p53. For p21, increased mRNA led to commensurately increased protein levels. In contrast, reduction in cyclin E2 mRNA levels did not lead to corresponding reductions in cyclin E2 protein. The proteasomal inhibitor MG-132 caused p53 protein to increase, but it had no effect on cyclin E2 protein levels. Cycloheximide time course studies indicated that the cyclin E2 protein half-life was more than 12 hours in these cells. CONCLUSIONS: Beryllium elicited p53-dependent changes in mRNA levels of key determinants of cell proliferation such as p21 and cyclin E2. However, cyclin E2 protein appeared to be aberrantly regulated in this cell type, as its turnover was unexpectedly slow.
Chen L, Luo L, Chen W, et al. MicroRNA-24 increases hepatocellular carcinoma cell metastasis and invasion by targeting p53: miR-24 targeted p53. Biomed Pharmacother. 2016; 84:1113-1118 [PubMed] Related Publications
MicroRNA-24 (miR-24), a member of the miRNA family, functions as an oncogene in various types of human cancer. However, the underlying mechanisms of miR-24 involvement in the development and progression of hepatocellular carcinoma (HCC) remain poorly understood. The present study revealed that miRNA-24 down-regulates p53 through binding to the 3'-UTR of p53 mRNA based on a luciferase reporter assay, and that the expression level of miR-24 could affect the invasion of HCC lines via p53. Down-regulation of p53 significantly attenuated the inhibitory effects of miR-24 knockdown on the invasion of HCC cells, suggesting that miR-24 could be a potential target for HCC treatment. Moreover, our results revealed that miR-24 expression was significantly increased in HCC metastatic tumor tissues compared with matched non-metastatic tumor tissues, and that the up-regulation of miR-24 was significantly associated with down-regulation of p53 in the HCC tissues. In conclusion, this study demonstrates that miR-24 functions as an oncogene in HCC, at least partly by promoting cell invasion through down-regulation of p53. Therefore, miR-24 may be a potential therapeutic target for treatment of HCC.
Yi L, Cui Y, Xu Q, Jiang Y Stabilization of LSD1 by deubiquitinating enzyme USP7 promotes glioblastoma cell tumorigenesis and metastasis through suppression of the p53 signaling pathway. Oncol Rep. 2016; 36(5):2935-2945 [PubMed] Related Publications
The substrates and mechanisms of ubiquitin specific peptidase 7 (USP7) in glioma remain unclear. Lysine‑specific demethylase 1 (LSD1) may undergo proteasomal degradation; however, a reciprocal mechanism that stabilizes LSD1 in glioma has not been dertermined. Here co-immunoprecipitation and GST pull-down assays revealed that LSD1 is associated with USP7 in vivo and in vitro. USP7 inhibited LSD1 ubiquitination and stabilized LSD1 in A172 and T98G cells. MTT, EdU proliferation, flow cytometry and Transwell assays indicated that LSD1 played a critical role in the proliferation and invasion of glioblastoma (GBM) cells. We defined the mechanism of USP7 in GBM, through counterbalanced LSD1 ubiquitylation. USP7 caused G0/G1 arrest, promoted tumorigenesis and invasion of A172 and T98G cells. We also uncovered the suppression of the p53 signaling pathway that mediated the activity of USP7 and LSD1. Furthermore, USP7 and LSD1 expression levels were higher in the 150 glioma patients than these levels in normal brain tissues and were correlated with glioma progression. LSD1 was increased concurrently with USP7 during glioblastoma progression and both were predictors for worsened prognosis. Collectively, our study suggested that USP7-LSD1 affects GBM cell proliferation and invasion and may be valuable as novel therapeutic targets and prognostic tools for GBM.
Swiatkowska A, Zydowicz P, Sroka J, Ciesiołka J The role of the 5' terminal region of p53 mRNA in the p53 gene expression. Acta Biochim Pol. 2016; 63(4):645-651 [PubMed] Related Publications
The p53 tumour suppressor protein is one of the major factors responsible for cell cycle regulation and protection against cancer development. This is why it is often referred to as "the guardian of the genome". On the other hand, mutations in the p53 gene are connected with more than 50% of tumours of various types. The thirty-six years of extensive research on the p53 gene and its protein products have shown how sophisticated the p53-based cell system control is. An additional level of complexity of the p53 research is connected with at least twelve p53 isoforms which have been identified in the cell. Importantly, disturbance of the p53 isoforms' expression seems to play a key role in tumorigenesis, cell differentiation and cell response to pathogenic bacteria, and RNA and DNA viruses. Expression of various p53 isoforms results from the usage of different transcription promoters, alternative splicing events and translation initiation from alternative AUG codons. The importance of the 5'-terminal regions of different p53 mRNA transcripts in the multi-level regulation of the p53 gene has recently been documented. In this review we focus on the structural features of these regions and their specific role in the p53 translation initiation process.
Tao Z, Chen S, Mao G, et al. The PDRG1 is an oncogene in lung cancer cells, promoting radioresistance via the ATM-P53 signaling pathway. Biomed Pharmacother. 2016; 83:1471-1477 [PubMed] Related Publications
PDRG1, is short for P53 and DNA damage-regulated gene, which have been found over 10 years. Although severe studies have described the roles of PDRG1 separately in many kinds of tumors, how to act as an oncogene are unclear. To better verify the function of PDRG1 in lung cancer, both loss-function and gain-function of PDRG1 studies based on two human lung cancer lines were performed. Following the transfection of PDRG1, both A549 and 95-D cells showed significant changes in cell viability, the expression of some protein and apoptosis, which were all implied the PDRG1 is an oncogene. Another interesting finding is PDRG1 could promote radioresistance involved the ATM-p53 signaling pathway in lung cancer. If we combine radiotherapy with gene-targeted therapy together effectively, predominant effect may be acquired, which is a huge milestone in clinical cure about lung cancer.
Nishida N, Kudo M Clinical Significance of Epigenetic Alterations in Human Hepatocellular Carcinoma and Its Association with Genetic Mutations. Dig Dis. 2016; 34(6):708-713 [PubMed] Related Publications
Accumulation of genetic and epigenetic alterations is a hallmark of cancer genomes, including those in hepatocellular carcinoma (HCC). Particularly, in human HCC, epigenetic changes are more frequently observed than genetic changes in a variety of cancer-related genes, suggesting a potential role for epigenetic alterations during hepatocarcinogenesis. Several environmental factors, such as inflammation, obesity, and steatosis, are reported to affect the epigenetic status in hepatocytes, which could play a role in HCC development. In addition, genetic mutations in histone modulators and chromatin regulators would be critical for the acceleration of epigenetic alteration. It is also possible that major genetic mutations of HCC, such as TP53 and CNTTB1 mutations, are associated with the disturbance of epigenetic integrity. For example, specific TP53 mutations frequently induced by aflatoxin B1 exposure might affect histone modifiers and nucleosome remodelers. Generally, epigenetic alteration is reversible, because of which dysregulation of transcription takes place, without affecting protein structure. Therefore, differentiation therapy is one of the potential approaches for HCC with advanced epigenetic alterations. On the other hand, a tumor carrying an accumulation of genetic mutations would result in many abnormal proteins that could be recognized as non-self and could be targets for immune reactions; thus, immune-checkpoint blockers should be effective for HCCs with genetic hypermutation. Although the emergence of genetic and epigenetic alterations could be linked to each other and there could be some crossover or convergence between these cancer pathways, characterization of the mutation spectrum of genetic and epigenetic alterations could influence future HCC treatment.
Wang J, Jiao Y, Cui L, Jiang L miR-30 functions as an oncomiR in gastric cancer cells through regulation of P53-mediated mitochondrial apoptotic pathway. Biosci Biotechnol Biochem. 2017; 81(1):119-126 [PubMed] Related Publications
The present study was designed to investigate the role of miR-30 in the development of Gastric cancer (GC). miR-30 expression was increased in GC tissues and cell lines. Downregulation of miR-30 inhibited cell proliferation and promoted apoptosis in HGC-27 cells. Upregulation of miR-30 enhanced the proliferation and inhibited apoptosis. P53 expression was decreased in GC tissues. P53 expression was correlated with miR-30 expression. Downregulation of miR-30 increased P53 expression. Knockdown of P53 inhibited miR-30-inhibitor-induced suppression of cell proliferation and increase of apoptosis. Downregulation of miR-30 increased ROS generation which was inhibited by shP53. miR-30 inhibitors induced a decrease in mitochondrial oxygen consumption, cytoplasmic release of cytochrome c, and activation of Caspase 3 and 9, activating mitochondrial apoptotic pathway. Downregulation of P53 and N-acetyl-cysteine suppressed miR-30 inhibitors-activated mitochondrial dysfunction and apoptotic events. In conclusion, we identified that miR-30 functioned as a potential oncomiR through P53/ROS-mediated regulation of mitochondrial apoptotic pathway.
Minervini CF, Cumbo C, Orsini P, et al. TP53 gene mutation analysis in chronic lymphocytic leukemia by nanopore MinION sequencing. Diagn Pathol. 2016; 11(1):96 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
BACKGROUND: The assessment of TP53 mutational status is becoming a routine clinical practice for chronic lymphocytic leukemia patients (CLL). A broad spectrum of molecular techniques has been employed so far, including both direct Sanger sequencing and next generation sequencing. Oxford Nanopore Technologies recently released the MinION an USB-interfaced sequencer. In this paper we report our experience, with the MinION technology for the detection of the TP53 gene mutation in CLL patients. Twelve CLL patients at diagnosis were included in this study. All except one patient showed the TP53 gene deletion in Fluorescence in situ hybridization experiments. Patients were investigated for TP53 mutation by Sanger and by MinION sequencing. Analysis by Sanger was performed according with the IARC protocol. Analysis by MinION was performed adopting a strategy based on long template PCR, read error correction, and post variant calling filtering. RESULTS: Due to the high error rate of nanopore technology, sequence data were both used directly and before correction with two different in silico methods: ALEC and nanocorrect. A mean error rate of 15 % was detected before correction that was reduced to 4-5 % after correction. Analysis by Sanger sequencing was able to detect four patients mutated for TP53. MinION analysis detected one more mutated patient previously not detected from Sanger. CONCLUSION: In our hands, the Nanopore technology shows correlation with Sanger sequencing but more sensitive, manageable and less expensive, and therefore has proven to be a useful tool for TP53 gene mutation detection.
Apsalikov B, Manambaeva Z, Ospanov E, et al. BRCA1 and TP53 Gene-Mutations: Family Predisposition and Radioecological Risk of Developing Breast Cancer. Asian Pac J Cancer Prev. 2016; 17(8):4059-62 [PubMed] Related Publications
Frequencies of polymorphisms of genes BRCA1 and TP53 in breast cancer (BC) patients with a BC family history and radiation history were assessed and compared in the Semey region of Kazakhstan. The study included 60 women directly irradiated by the activities of the Semipalatinsk test site with a calculated effective equivalent dose of 500 mSv and their first generation descendants (group BC+Her+Exp); 65 women with family BC and absence of radiological history - the effective equivalent dose due to anthropogenic sources not exceeding 50 mSv (group BC+Her-Exp). The comparison group consisted of 65 women patients with breast cancer without family and radiological history (BC-Her-Exp). The control group comprised 60 women without breast cancer and without family and radiological history (nonBC). We carried out the genotyping of the polymorphisms c.2311T>C, c.4308T>C and 5382insC of the BRCA1 gene and rs1042522 of the TP53 gene. The frequency of the polymorphism c.2311T>C was significantly higher in patients of the group BC+Her+Exp than in healthy women, and of the polymorphism 5382insC in BC+Her+Exp compared to all other groups. The frequency of the rs1042522 polymorphism of TP53 was significantly higher in all groups of patients with breast cancer compared with the control group. Differences between groups of women with breast cancer were significant only in BC+Her+Exp vs. BC+Her-Exp. Combinations of polymorphisms of the genes BRCA1 and TP53 predominated in women with a family and radiological history.
Shin K, Kim KH, Yoon MS, et al. Expression of Interactive Genes Associated with Apoptosis and Their Prognostic Value for Ovarian Serous Adenocarcinoma. Adv Clin Exp Med. 2016 May-Jun; 25(3):513-21 [PubMed] Related Publications
BACKGROUND: Malignant ovarian tumor is one of the leading causes of worldwide cancer death. It is usually characterized by insidious onset and late diagnosis because of the absence of symptoms, allowing ovarian cancer cases to progress rapidly and become unresectable. The tumor suppressor, p53, plays an important role in regulating cell cycles and apoptosis. p53 is regulated by several molecules, and it interacts with other apoptotic proteins. OBJECTIVES: To compare the prognosis of ovarian serous carcinoma and evaluate the expression of DNA-PKcs, Akt3, GSK-3β, and p53 in cancerous cells. MATERIAL AND METHODS: DNA-PKcs, Akt3, GSK-3β, and p53 expression levels were scored using immunohistochemistry staining of tissue samples from 132 women with ovarian serous adenocarcinoma. Expression was confirmed by real-time RT-PCR. Analyses were stratified by age, tumor grades, cancer stages and serum CA 125 levels. RESULTS: Significant differences in DNA-PKcs, Akt3, and p53 expression were observed between participants with different stages and tumor grades of ovarian serous adenocarcinoma. DNA-PKcs and p53 expression increased along with increasing tumor grade. Meanwhile, DNA-PKcs, Akt3, and p53 expression increased along with increasing cancer stage, and with a decrease in 5-year overall survival rate. CONCLUSIONS: This study shows that elevated expression of DNA-PKcs, Akt3, and p53 in ovarian serous adenocarcinoma tissues are an indication of more advanced disease and worse prognosis.
Arora H, Qureshi R, Rizvi MA, et al. Study of apoptosis-related interactions in colorectal cancer. Tumour Biol. 2016; 37(11):14415-14425 [PubMed] Related Publications
Abnormalities in apoptotic functions contribute to the pathogenesis of colorectal cancer. In this study, molecular interactions behind the apoptotic regulation have been explored. For this purpose, enrichment analysis was performed considering microRNAs (miRNAs) that putatively target TP53 and altered during colon cancer. This revealed gene associated with both TP53 and miRNAs. Further analysis showed that a significant molecular interaction between the shortlisted candidates (TP53, miR-143, KRAS, BCL2, and PLK1) exists. Mutation study was conducted to confirm the clinical relevance of candidates. It showed that the mutation extent does not significantly alter survival in patients thus making these candidates suitable as drug targets. Overall, we showed the importance of interactions between TP53, miR-143, KRAS, BCL2, and PLK1 with respect to colorectal cancer using bioinformatics approach.
Endo A, Tomizawa D, Aoki Y, et al. EWSR1/ELF5 induces acute myeloid leukemia by inhibiting p53/p21 pathway. Cancer Sci. 2016; 107(12):1745-1754 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
The Ewing sarcoma breakpoint region 1 (EWSR1) gene is known to fuse with various partner genes to promote the development of the Ewing sarcoma family of tumors and other sarcomas. In contrast, the association of EWSR1 chimeric fusion genes with leukemia has rarely been reported. We identified a novel EWSR1-associated chimeric fusion gene in a patient with acute myeloid leukemia harboring 46, XY, t (11; 22) (p13; q12) karyotype abnormality. The patient was refractory to intensified chemotherapy including hematopoietic stem cell transplantation. Total RNA paired-end sequencing identified a novel chimeric fusion gene as EWSR1/ELF5, a member of the E26 transformation-specific transcription factor family. Transduction of EWSR1/ELF5 to NIH3T3 cells induced transformation by attenuating with the p53/p21-dependent pathway. The injection of EWSR1/ELF5-transduced NIH3T3 cells into NSG-SCID mice systematically induced the development of tumors in vivo. These results revealed the oncogenic potency of EWSR1/ELF5.
Kumari A, Bahl C, Singh N, et al. Association of p53 codon 72 polymorphism and survival of North Indian lung cancer patients treated with platinum-based chemotherapy. Mol Biol Rep. 2016; 43(12):1383-1394 [PubMed] Related Publications
p53 helps in maintaining genomic stability by undergoing cellular arrest, DNA repair or cellular apoptosis during DNA damage. So, as to find the association of p53Arg (72) Pro towards lung carcinogenesis and overall survival of North Indian lung cancer patients, single nucleotide polymorphic variant (rs1042522) was analyzed. 840 subjects including 420 cases and 420 controls were recruited and genotyped using PCR-RFLP technique for p53Arg (72) Pro polymorphic site. Association was analyzed using adjusted odds ratio along with its confidence intervals (95 % CI) and p value predicted from logistic regression whereas overall survival for lung cancer patients was obtained using Kaplan-Meir and Cox regression model for different parameters to obtain hazard ratio and survival time with statistical significance (log-rank p value). None of the variant genotypes for p53Arg (72) Pro showed any association towards lung cancer risk or any specific histological subtype. Lung cancer subjects with Pro/Pro genotype had better median survival time as compared to Arg/Pro genotype (10 months; HR = 0.65; 95 % CI = 0.45-0.95; p = 0.03). Furthermore, female lung cancer patients with Arg/Pro (HR = 0.08; 95 % CI = 0.02-0.34; p = 0.0005) and Pro/Pro (HR = 0.21; 95 % CI = 0.06-0.67; p = 0.008) genotypes showed a better overall survival and hence a better prognosis as compared to males. Our data also reveals that lung cancer patients with ECOG scores between 0 and 1 and carrying the Pro/Pro had better chances of survival. p53 codon 72 polymorphism could play a role as a prognostic marker in lung cancer patients.
Wang H, Li W, Lai B, et al. Role of 3' repressor sequences of p53 in anti-cancer drug sensitivity of human lung tumor cells. Gene. 2016; 594(2):190-196 [PubMed] Related Publications
INTRODUCTION: The C-terminus of p53 and non-coding mRNAs play critical roles in negative regulation. However, their impact on anti-cancer drug sensitivity remains unclear. METHODS: In this study, we investigated the effects of p53 deleting these sequences on anti-cancer drug sensitivity by drug sensitivity test, flow cytometry, Agilent mRNA expression microarray detection, transplantation tumor in nude mice. RESULTS: The results showed that the cell line with p53 deleted the C-terminal sequences (p53(del)) was more sensitive to navelbine (NVB) compared to the cell line that carried the full length p53 (p53(wt)). The p53(del) cells was more sensitive to cisplatin (PDD) and 5-fluorouracil (5FU) than p53(wt) cells but there was not significant difference. NVB treatment led to significant G2 arrest and apoptosis in p53(del) cells but not in p53(wt) cells. mRNA expression profile of p53(del) cells indicated that approximately 11% of the 41,000 genes in genome showed differential expression after NVB treatment, among which 2064 genes were up-regulated and 2784 were down-regulated with fold change >2 (P<0.01). Tumor transplantation assay in nude mice showed that the p53 truncation significantly increased tumor sensitivity to NVB compared to the full-length p53, with 99.46% tumor inhibition. CONCLUSIONS: In summary, deletion of 37 amino acid residues (356-393) and 3' non-coding mRNAs at the C-terminus of p53 selectively increased tumor sensitivity to the mitotic inhibitor NVB.
Eydian Z, Asna'ashari AM, Behravan J, et al. Association of P53 codon 72 polymorphism and lung cancer in an ethnic Iranian population. Cell Mol Biol (Noisy-le-grand). 2016; 62(9):34-8 [PubMed] Related Publications
Lung cancer is one of the most common causes of cancer death worldwide. Molecular genetic studies indicated that activation of dominant oncogenes or inactivation of tumor suppressor genes and the presence of polymorphism in these genes correlated with prevalence of new lung cancers. P53 as a tumor suppressor gene located at 17p13 chromosome and it is one of the most well-known mutant genes in all cancer types. Mutation in P53 can disturb the transcriptional function and suppression of cell cycle control and increase in cell division and amplification. We can predict the susceptibility of people inside a society to lung cancer with evaluation of P53 gene polymorphism. A total of 200 patients with lung cancer and 200 healthy controls participated in this case-control study. Genomic DNA was extracted from blood samples and PCR-RFLP analyses were used to genotype the P53 gene polymorphism in codon 72 of exon 4, chromosome 17. Among 200 lung cancer patients and 200 controls, there was no significant correlation between sexuality and cigarette smoking status. We did not find any relationship between cigarette smoking status and genotypes or pack-years but there was a significant correlation between cigarette smoking status and adenocarcinoma patients (P=0.03). The results of the present study revealed that there is no association between P53 codon 72 polymorphism and increased risk of lung cancer in patients and controls but according to results of adenocarcinoma in never-smoker patients, it seems that environmental factors may have more important role than genetic susceptibility in our ethnic Iranian population.
Moroni M, Stella M, Pedrazzoli P, et al. c.428T > C (p.V143A) homozygous mutation in TP53 gene as a possible mechanism of resistance to trastuzumab therapy in gastric cancer. Acta Oncol. 2016; 55(11):1373-1375 [PubMed] Related Publications
Popp C, Nichita L, Voiosu T, et al. Expression Profile of p53 and p21 in Large Bowel Mucosa as Biomarkers of Inflammatory-Related Carcinogenesis in Ulcerative Colitis. Dis Markers. 2016; 2016:3625279 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease that slightly increases the risk of colorectal cancer in patients with long-standing extended disease. Overexpression of p53 and p21 in colonic epithelia is usually detected in UC patients when no dysplasia is histologically seen and it is used by pathologists as a discriminator between regenerative changes and intraepithelial neoplasia, as well as a tissue biomarker useful to predict the risk of evolution toward malignancy. We present a one-year prospective observational study including a cohort of 45 patients with UC; p53 and p21 were evaluated in epithelial cells. p53 was positive in 74 samples revealed in 5% to 90% of epithelial cells, while 63 biopsies had strong positivity for p21 in 5% to 50% of epithelial cells. Architectural distortion was significantly correlated with p53 overexpression in epithelial cells. Thus, we consider that architectural distortion is a good substitute for p53 and p21 expression. We recommend use of p53 as the most valuable tissue biomarker in surveillance of UC patients, identifying the patients with higher risk for dysplasia. Association of p21 is also recommended for a better quantification of risk and for diminishing the false-negative results.
Arfaoui A, Douik H, Kablouti G, et al. MDM2 344T>A polymorphism; could it be a predictive marker of anthracycline resistance? J BUON. 2016 May-Jun; 21(3):732-9 [PubMed] Related Publications
PURPOSE: To find a possible association between the Mouse Double Minute 2(MDM2) 344T>A, alone and in combination with p53 72 Arg/Pro polymorphism, and resistance to anthracycline-based chemotherapy of breast cancer in Tunisia. METHODS: This study enrolled 542 patients with invasive ductal carcinoma (IDC) treated with anthracycline-based chemotherapy. Genomic DNA was isolated from whole blood, using the phenol chloroform method. Anthracycline response was scored according to the World Health Organization (WHO). MDM2 344T>A polymorphism was genotyped using real time polymerase chain reaction (RT-PCR) with the TaqMan method. Data was statistically analyzed using the x2 test. RESULTS: Response was evaluated in 400 patients, of whom a quarter was found to be resistant to chemotherapy. Genetic data revealed that resistance to anthracycline-based chemotherapy did not seem to be correlated with 344T>A polymorphism in the studied population. Also, no significant association was found between the single nucleotide polymorphism (SNP) 344T>A status and clinicopathologic parameters (p>0.05 for all comparisons). Moreover, analysis of p53 rs1042522 and MDM2 rs1196333 combination showed no significant association between these two genetic variants and anthracycline resistance (p=0.2). CONCLUSIONS: Our findings provide no evidence indicating that SNP 344 T>A may affect response to anthracycline-based chemotherapy. However, the results obtained from the combination of SNPs 344T>A of MDM2 and 72 Arg/Pro of p53, do not support the hypothesis of the prominent role of common p53 and MDM2 variations in the genetic mechanisms of chemotherapy resistance in breast cancer.