Antisense oligonucleotide-mediated inhibition of mutant p53 expression

1996 ◽  
Vol 24 (3) ◽  
pp. 410S-410S ◽  
Author(s):  
Carolyn J. Ruddell ◽  
John A. Green ◽  
David M. Tidd
Keyword(s):  
Antisense Oligonucleotide ◽  
Mutant P53 ◽  
P53 Expression

scholarly journals Mutant P53 Expression Of Oral Transformed Epithelium Cell In Rats Injected By Benzo[A]Pyrene

2020 ◽  
Vol 9 (1) ◽  
pp. 85-92
Author(s):  
Sawitri Dwi indah Pertami ◽  
I Ketut Sudiana ◽  
Theresia Indah Budhy ◽  
Retno Palupi ◽  
Ira Arundina
Keyword(s):  
Cell Transformation ◽  
Control Group ◽  
Mutant P53 ◽  
P53 Expression ◽  
Dna Mutation ◽  
Treatment Groups ◽  
Epithelium Cell ◽  
Polycyclic Aromatic ◽  
The One ◽  
Epithelium Cells

Benzopyrene is a polycyclic aromatic hydrocarbons (PAHs) compound that can cause transformation of normal cells into malignant in order to its genotoxic,mutagenic,and carsinogenic ability.  DNA mutation in tumor suppressor genes p53 make cells immortal which results in cell transformation and develops into malignancies. This study consist of five groups including the control group (without benzopyrene injection) and 4 treatment groups injected with benzopyrene each for 4 weeks (P1), 6 weeks (P2), 8 weeks (P3) and 10 weeks (P4).  Therefore, the mutant p53 expression was calculated and analyzed statistically with the One Way Anova Test. There was signifficance difference in mutant p53 expression of oral transformed epithelium cell injected by benzopyrene (p=0.000) and the highest expression was at 10th week. It can be concluded that the mutant P53 expression of oral transformed epithelium cells in rats was increased after injected by benzopyrene

scholarly journals MBRS-18. TUMOR SUPPRESSOR p53 DEFINES THE THERAPEUTIC RESPONSES IN TREATMENT OF MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii401-iii401
Author(s):  
Avinash L Mohan ◽  
Anubhav G Amin ◽  
Michael E Tobias ◽  
Mohan K Das ◽  
Raphael S S de Medeiros ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Disease Progression ◽  
Combined Treatment ◽  
Metastatic Potential ◽  
Mutant P53 ◽  
P53 Expression ◽  
P53 Signaling ◽  
Mutational Status ◽  
Gli 1

Abstract Medulloblastoma (MB) is the most common primary pediatric malignant brain tumor. Current molecular analysis classifies MB into 4 groups, classic (WNT), sonic hedgehog (Shh), group 3, and group 4. Furthermore, atypical p53 signaling is associated with disease progression and confers poor prognosis. This study investigated the correlation of mutational status of p53 and iSO17q with disease progression and metastatic potential. In addition, we used small molecule inhibitors of PI3K (Buparlisib; BKM120) and HDAC (LBH-589) on a p53-mutant MB cell line to find novel therapeutic targets. Efficacy of these drugs were assessed using functional assays (cell proliferation, migration, cell cycle and drug resistance). MB tumors (n=53) were evaluated for GLI-1, GAB-1, NPR, KV1, YAP expression and mutant p53 via immunohistochemistry and correlated to patient outcomes. Results demonstrated that: 1) high expression of GAB-1 and YAP were found in the Shh group, while KV1 expression was present in all subtypes; 2) mutant p53 expression was present in various subsets of MB with no apparent correlation with metastasis or disease progression; 3) patients displaying iSO17q (determined by fluorescence in situ hybridization (FISH) technique) exhibited metastatic disease; 4) LBH-589 and BKM120 caused both time and dose-dependent inhibition of MB cell proliferation and migration; 5) combined treatment of BKM120 and LBH-589 had a synergistic effect; 6) MB cells demonstrated drug-resistance to BKM120. In conclusion, these findings underscore use of Buparlisib and LBH-589 in treatment of MB. Further, the role of mutant p53 in disease progression remains elusive, whereas presence of iSO17q defines metastatic potential.

scholarly journals Mutant p53 and Twist1 Co-Expression Predicts Poor Prognosis and Is an Independent Prognostic Factor in Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Yong-Qu Zhang ◽  
Fan Zhang ◽  
Yun-Zhu Zeng ◽  
Min Chen ◽  
Wen-He Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Clinical Stage ◽  
Lymph Node Involvement ◽  
Mutant P53 ◽  
Breast Cancer Patients ◽  
P53 Expression ◽  
Free Survival ◽  
Node Involvement ◽  
Patient Prognosis

PurposeThe basic helix-loop-helix transcription factor (bHLH) transcription factor Twist1 plays a key role in embryonic development and tumorigenesis. p53 is a frequently mutated tumor suppressor in cancer. Both proteins play a key and significant role in breast cancer tumorigenesis. However, the regulatory mechanism and clinical significance of their co-expression in this disease remain unclear. The purpose of this study was to analyze the expression patterns of p53 and Twist1 and determine their association with patient prognosis in breast cancer. We also investigated whether their co-expression could be a potential marker for predicting patient prognosis in this disease.MethodsTwist1 and mutant p53 expression in 408 breast cancer patient samples were evaluated by immunohistochemistry. Kaplan-Meier Plotter was used to analyze the correlation between co-expression of Twist1 and wild-type or mutant p53 and prognosis for recurrence-free survival (RFS) and overall survival (OS). Univariate analysis, multivariate analysis, and nomograms were used to explore the independent prognostic factors in disease-free survival (DFS) and OS in this cohort.ResultsOf the 408 patients enrolled, 237 (58%) had high mutant p53 expression. Two-hundred twenty patients (53.9%) stained positive for Twist1, and 188 cases were Twist1-negative. Furthermore, patients that co-expressed Twist1 and mutant p53 (T+P+) had significantly advanced-stage breast cancer [stage III, 61/89 T+P+ (68.5%) vs. 28/89 T-P- (31.5%); stage II, 63/104 T+P+ (60.6%)vs. 41/104 T-P- (39.4%)]. Co-expression was negatively related to early clinical stage (i.e., stages 0 and I; P = 0.039). T+P+ breast cancer patients also had worse DFS (95% CI = 1.217–7.499, P = 0.017) and OS (95% CI = 1.009–9.272, P = 0.048). Elevated Twist1 and mutant p53 expression predicted shorter RFS in basal-like patients. Univariate and multivariate analysis identified three variables (i.e., lymph node involvement, larger tumor, and T+P+) as independent prognostic factors for DFS. Lymph node involvement and T+P+ were also independent factors for OS in this cohort. The total risk scores and nomograms were reliable for predicting DFS and OS in breast cancer patients.ConclusionsOur results revealed that co-expression of mutant p53 and Twist1 was associated with advanced clinical stage, triple negative breast cancer (TNBC) subtype, distant metastasis, and shorter DFS and OS in breast cancer patients. Furthermore, lymph nodes status and co-expression of Twist1 and mutant p53 were classified as independent factors for DFS and OS in this cohort. Co-evaluation of mutant p53 and Twist1 might be an appropriate tool for predicting breast cancer patient outcome.

scholarly journals Expression of Wild-Type p53 by Curcumin, Alpinetin and Flavokawain B in Colorectal Cancer cells Expressing R273H Mutant p53

2020 ◽  
Vol 27 (2) ◽  
pp. 88-94
Author(s):  
I. Malami ◽  
A. Muhammad ◽  
I.B. Abubakar ◽  
A.M. Alhassan
Keyword(s):  
Bioactive Compounds ◽  
Mutant P53 ◽  
Wild Type ◽  
P53 Expression ◽  
Gene And Protein Expression ◽  
Colorectal Cancer Cells ◽  
Binding Core ◽  
Wild Type P53 ◽  
Dose Dependent

A mutation in p53 is frequently reported in nearly 50% of all of human cancers arising from DNA-binding core domain of p53. DNA-contact mutant R273H rendered p53 at dysfunctional state due to the substitution of single residue Arg273 for His273. Here, natural bioactive compounds curcumin, alpinetin and flavokawain B were investigated for possible stabilisation of wild-type p53 expression in vitro using HT-29 cells harbouring R273H rendered p53. Accordingly, all the bioactive compounds were able to induce the expression of wild-type p53 both at the levels of gene and protein expression. A dose-dependent induction of p53 was evident at 12.5, 25 and 50 μM concentration. The present study has shown that the bioactive compounds may have restored the wild-type p53 functional activity in tumour cells expressing R273H mutant p53. Keywords: Curcumin, Alpinetin, Flavokawain B, p53, R273H

15-lipoxygenase-1 expression in prostate cancer: Correlation with mutant P53 expression and histologic grade

1999 ◽  
Vol 59 (1-6) ◽  
pp. 54
Author(s):  
Uddhav P. Kelavkar ◽  
Cynthia Cohen ◽  
Thomas E. Eling ◽  
Kamal F. Badr
Keyword(s):  
Prostate Cancer ◽  
Histologic Grade ◽  
Mutant P53 ◽  
P53 Expression

High p53 Protein Expression LEVEL Independent Of Mutational Status Is An Adverse Prognostic Factor For Survival In ACUTE Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1330-1330
Author(s):  
Alfonso Quintas-Cardama ◽  
Sean M. Post ◽  
Kensuke Kojima ◽  
Yi Hua Qiu ◽  
Michael Andreeff ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutant P53 ◽  
P53 Mutations ◽  
Wild Type ◽  
P53 Pathway ◽  
P53 Expression ◽  
Mutational Status ◽  
Wild Type P53 ◽  
Acute Myeloid

Abstract Background The tumor suppressor p53 is frequently mutated in human cancer, including acute myeloid leukemia (AML), particularly in cases with high-risk cytogenetics. It has been shown that p53 stabilization, which frequently occurs when the protein is mutated, can compromise its function. We have shown that p53 stabilization, regardless of the presence of mutations, suggesting alterations of other components in the p53 pathway. Methodology p53 expression was determined using high-throughput reverse phase protein array (RPPA) technology in 719 samples from 511 pts. Eleven CD34+ bone marrow (BM) and 10 normal peripheral blood (PB) lymphocyte samples were used as controls. Samples were printed as 5 serial 1:2 dilutions in duplicate using an Aushon 2470 Arrayer. Mutational status of p53 alleles was assessed by Sanger sequencing of exons 5 through 9. Expression of components of the p53 pathway was determined using standard immunohistochemical techniques. Nutlin-3a was used in in vitro culture experiments. Results Paired PB- and BM-derived AML samples expressed similar p53 levels (p=0.25). A trend towards higher p53 expression at relapsed was observed among 47 paired diagnosis/relapse samples (p=0.07). p53 expression correlated directly with CD34 (p=0.001) and inversely correlated with WBC (p=0.007), PB and BM blast burden (p=0.0001), and survival (p=0.01). High p53 (p53high) expression was more associated with unfavorable cytogenetics, particularly -5 (p=0.00001). p53high resulted in lower complete remission (CR) rates (51% vs 56%; p=??), higher relapsed rates (82% vs 62%; p=??), and shorter median overall survival (OS; 29.8 vs. 51 wks, p=0.009) compared to p53low pts. Most cases with p53high had unfavorable cytogenetics. We next correlated p53 stabilization with the presence of p53 mutations in 68 pts. p53 mutations were detected in 20/54 (37%) p53high pts and in 0/14 (0%) pts with p53low. p53high, either in the presence (29 wks) or in the absence (24 wks) of p53 mutations (p=1.0), was associated with significantly shorter OS compared with p53low pts (56 wks; p=0.05). Multivariate analysis revealed p53 expression to be an independent risk factor for survival in AML (p=0.02). p53high was positively correlated with p53pSER15 (p=0.00001), Rbp807p811 (p=0.0002), BAD (p=0.0001), cleaved PARP (p=0.002), and cleaved PARP (p=0.01), and negatively with p21 (p=0.01), and MDM2 (p=0.001).Given the similar OS in p53high pts carrying mutant or wild-type p53, we scored the immunohistochemical expression of MDM2, MDM4, and p21 in 30 p53high pts (9 p53 mutated, 21 wild-type p53). Overexpression of MDM2 was observed in 44% vs 48% pts with mutant vs wild-type p53, respectively, whereas rates were 67% vs 62% for MDM4, and 0% vs 19% for p21, for each respective genotype. Overall, of the 21 p53high pts carrying wild-type p53, 15 (71%) had overexpression of MDM2 and/or MDM4, whereas 81% had no p21 expression, indicating deficient activation of the p53 pathway similar to those cases carrying mutant p53. We are currently assessing response to nutlin-3a therapy in 24 primary AML samples (4 mutant p53, 20 wild-type p53). Results showing the impact of p53 mutation and/or stabilization, and expression levels of MDM2, MDM4, and p21 on nutlin-3a therapy will be presented. Conclusions p53 stabilization (p53high) is a powerful predictive and prognostic factor in AML, which is independent of the presence of mutant p53 alleles. Poor outcomes in pts with p53high lacking p53 mutations are very frequently associated with overexpression of negative regulators of p53 such as MDM2 and/or MDM4 and p21 downregulation, indicating a functionally altered p53 pathway. These findings may have implications for therapies targeting the MDM2/p53 axis in AML. Disclosures: No relevant conflicts of interest to declare.

Tumor progression and chemoradiosensitivity in relation to the expression of apoptosis related proteins in esophageal squamous cell carcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4588-4588
Author(s):  
S. Tsujitani ◽  
H. Saito ◽  
S. Tatebe ◽  
M. Ikeguchi
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Survival Rates ◽  
Mutant P53 ◽  
Survivin Mrna ◽  
P53 Expression ◽  
Significant Difference ◽  
Related Proteins

4588 To study apoptosis related protein expression and their impact on patient’s survival time and sensitivity to postoperative chemoradiotherapy (CRT), we examined the expression of RB, mutant p53, MDM2 and Bax proteins using immunohistochemistry in 115 (CRT; 42) surgically resected esophageal squamous cell carcinoma (ESCC). We also investigated the survivin mRNA expression with quantitative analysis by real-time RT-PCR in 57 (CRT; 30) patients with ESCC. CRT contained 40–60 Gy radiation and continuous infusion of 5-FU (300mg/sqm, day1–5qw). Expression of RB, mutant p53, MDM2, Bax proteins and survivin mRNA were detected in 65%, 46%, 33%, 37% and 32% of patients, respectively. Patients with RB(+), MDM2(-), Bax(+) or survivin(-) tumor had significantly better survival rates than those with RB(-), MDM2(+), Bax(-) or survivin(+) tumor, respectively. However, there was no significant difference in survival between patients with and without mutant p53 expression. In patients not treated with CRT, those with RB(+) or survivin(-) tumor survived significantly longer than those with RB(-) or survivin(+) tumor, respectively. In patients treated with CRT, the expression of Bax protein and survivin mRNA was prognostic indicator. The 5-year survival rates of patients with Bax(+) and survivin(-) tumors were 65% and 39%, significantly superior to 21% and 0% of those with Bax(-) and survivin(+) tumors (P<0.05 and P<0.01, respectively). These results indicate that the expression levels of apoptosis related proteins are important for predicting the prognosis of ESCC patients. Furthermore, CRT may be effective in patients with Bax(+) or survivin(-) tumors. Further investigations are required for clarifying the relationship between the efficacy of postoperative CRT and apoptosis promoting status of ESCC. No significant financial relationships to disclose.

The prognostic value of P53 in the nodal metastization of gastric cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14673-e14673
Author(s):  
Luisa Quaresma ◽  
Antonio CALDEIRA Fradique ◽  
Fernanda Cabrita ◽  
Alexandra Pupo ◽  
Guedes DA Silva ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Lymph Node ◽  
Prognostic Factor ◽  
Gastric Carcinoma ◽  
Lymph Node Metastases ◽  
P53 Protein ◽  
Mutant P53 ◽  
P53 Expression ◽  
Major Interest ◽  
Node Metastases

e14673 Background: Lymph node Metastases play a major role as an independent prognostic factor in gastric cancer. Presence of distal lymph node metastases assumes a pejorative prognostic significance, and represents a problem in terms of therapeutic approach. For this reason it’s of major interest to find predictive markers of distal lymph node chain involvement. The P53 tumor suppressor gene, a product of the TP53 gene works normally as a brake on DNA replication, as suppressor of angiogenesis and triggering of apoptosis. The gene most frequently mutated in gastric cancer is the TP53, that is responsible for the production of P53 mutant protein, which forms inactive complex with the native protein, and manifest by the overexpression of p53 in immunocytochemistry. The overexpression of P53 gene has been considered a bad prognostic factor associated mainly with lymph node metastases. Methods: This study seeks to determine the relation between the expression of P53 and the presence of distal lymph node metastases as an indicator for an extended lymphadenectomy. A total of 50 patients undergoing surgery with D2 lymphadenectomy for gastric carcinoma with curative intent were enrolled in this work. Therefore it was evaluated in 1,786 lymph nodes the correlation between the P53 expression with tumor location, size, histological type, depth , number of nodes involved, number of distal lymph node metastases and the TNM stage. Results: In all parameters, mutant P53 protein related with indicators of poor prognosis. In particular has demonstrated a statistical significant correlation (p=0.019) with the presence of distal lymph node metastases. The main objective of this study which was finding a prognostic predictor of distal nodal metastases has been reached. Conclusions: Mutant P53 protein is a good prognostic indicator, for the presence of distal lymph node involvement in gastric carcinoma.

Sign in / Sign up

Export Citation Format

Share Document