scholarly journals Evidence for allosteric variants of wild-type p53, a tumour suppressor protein

1990 ◽  
Vol 61 (4) ◽  
pp. 548-552 ◽  
Author(s):  
A Cook ◽  
J Milner
Keyword(s):  
Tumour Suppressor ◽  
Wild Type ◽  
Tumour Suppressor Protein ◽  
Wild Type P53

scholarly journals Wild-type p53 binds to MYC promoter G-quadruplex

2016 ◽  
Vol 36 (5) ◽  
Author(s):  
Marek Petr ◽  
Robert Helma ◽  
Alena Polášková ◽  
Aneta Krejčí ◽  
Zuzana Dvořáková ◽  
...  
Keyword(s):  
Target Genes ◽  
Promoter Sequence ◽  
Tumour Suppressor ◽  
Wild Type ◽  
Quadruplex Dna ◽  
Tumour Suppressor Protein ◽  
G Quadruplex ◽  
Wild Type P53 ◽  
P53 Target Genes

We found that the p53 tumour suppressor protein binds specifically to the G-quadruplex DNA formed by MYC promoter sequence. We propose that p53 binding to G-quadruplexes can participate in regulation of p53 target genes.

Molecular analysis of different allelic variants of wild-type human p53

1992 ◽  
Vol 70 (10-11) ◽  
pp. 1014-1019 ◽  
Author(s):  
France Moreau ◽  
Greg Matlashewski
Keyword(s):  
Cultured Cells ◽  
Human Cancer ◽  
P53 Protein ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Allelic Variant ◽  
Wild Type ◽  
Allelic Variants ◽  
Wild Type P53

The p53 tumour suppressor gene is intensively studied because mutations in this gene are the most common genetic alteration so far identified in human cancer. Considerable emphasis has thus been placed on characterizing the biological differences between mutant and wild-type p53 protein. This has led to the realization that in cultured cells, mutant p53 behaves like an oncogene, whereas wild-type p53 is a tumour suppressor gene. The p53 protein is also a target for the tumour virus oncogene products SV40 large T, adenovirus E1B, and human papillomavirus type 16 E6, which are all capable of forming complexes to the p53 protein. Although p53 represents an extremely important cellular regulatory molecule which is well conserved, there exists two allelic variants of wild-type human p53 that differ both in primary and confirmational structure. One variant contains an arginine at amino acid 72 (p53Arg), whereas the other form contains a proline at this residue (p53Pro). The possible implications for more than one allelic variant of wild-type human p53 in the general population is unknown. The present study was undertaken to compare some of the biological features of the different wild-type p53 variants. We present data demonstrating that there was a post-transcriptional selection against accumulation of both variants of wild-type human p53 in 3T3-A31 cells, arguing that both forms are proliferation inhibitory in these cells. Both variants of human p53 were stabilized by SV40 large T, but did not displace mouse p53 from SV40 large T. Neither allelic variant of human p53 was able to reduce significantly SV40-mediated anchorage-independent growth of 3T3-A31 cells. Taken together, these data suggest that although there are structurally different variants of wild-type human p53, there is no difference in the biological activity of these molecules at the level of the biological assays performed here.Key words: human p53, large T, transformation, oncogenes, tumour suppressor.

scholarly journals Cellular Distribution of Tumour Suppressor Protein p53 and High-Risk Human Papillomavirus (HPV)-18 E6 Fusion Protein in Wild-Type p53 Cell Lines

2008 ◽  
Vol 36 (5) ◽  
pp. 1015-1021 ◽  
Author(s):  
L Sun ◽  
G Gzhang ◽  
Z Li ◽  
T Lei ◽  
C Huang ◽  
...  
Keyword(s):  
High Risk ◽  
Fluorescent Protein ◽  
P53 Protein ◽  
Expression System ◽  
Human Papillomaviruses ◽  
Tumour Suppressor ◽  
Wild Type ◽  
Hpv E6 ◽  
Wild Type P53 ◽  
High Risk Hpv

Human papillomaviruses (HPVs) are very important pathogens that can be classified as high- and low-risk types based on the lesions they cause. Mucosal high-risk HPV E6 can target and degrade the tumour suppressor p53, hence it is recognized as the major cause of cervical cancer, however, due to a lack of reliable anti-E6 antibodies, the distribution of high-risk HPV E6 protein remains elusive. The present study, therefore, used a mammalian green fluorescent protein (GFP) expression system to express GFP-18 E6 fusion proteins in wild-type p53 cells, SMMC-7721 and HCT116, in order to trace the location and expression of HPV E6 and p53 protein. Following transfection, expression of GFP-18 E6 was found to be located in the nucleus, and endogenous wild-type p53 was also located there with GFP-18 E6.

scholarly journals Revisiting the identification of breast cancer tumour suppressor genes defined by copy number loss of the long arm of chromosome 16.

2021 ◽  
Author(s):  
David Frederick Callen
Keyword(s):  
Hot Spots ◽  
Single Copy ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Breast Cancers ◽  
Wild Type ◽  
Chromosome 16 ◽  
Partial Loss ◽  
Suppressor Genes ◽  
Wild Type P53

In breast cancer loss of the long-arm of chromosome 16 is frequently observed, suggesting this is the location of tumour suppressor gene or genes. Previous studies localised two or three minimal regions for the LOH genes in the vicinity of 16q22.1 and 16q24.3, however the identification of the relevant tumour suppressor genes has proved elusive. The current availability of large datasets from breast cancers, that include both gene expression and gene dosage of the majority of genes on the long-arm of chromosome 16 (16q), provides the opportunity to revisit the identification of the critical tumour suppressor genes in this region. Utilising such data it was found 37% of breast cancers are single copy for all genes on 16q and this was more frequent in the luminal A and B subtypes. Since luminal breast cancers are associated with a superior prognosis this is consistent with previous data associating loss of 16q with breast cancers of better survival. Previous chromosomal studies found a karyotype with a der t(1;16) to be the basis for a proportion of breast cancers with loss of 16q. Use of data indicating the dosage of genes 21.9% of breast cancers were consistent with a der t(1;16) as the basis for loss of 16q. In such cases there is both loss of one dose of 16q and three doses of 1q suggesting a tumour suppressor function associated with long-arm of chromosome 16 and an oncogene function for 1q. Previous studies have approached the identification of tumour suppressor genes on 16q by utilising breast cancers with partial loss of 16q with the assumption regions demonstrating the highest frequency of loss of heterozygosity pinpoint the location of tumour suppressor genes. Sixty one of 816 breast cancers in this study showed partial loss of 16q defined by dosage of 357 genes. There was no compelling evidence for hot-spots of localised LOH which would pinpoint major tumour suppressor genes. Comparison of gene expression data between various groups of breast cancers based on 16q dosage was used to identify possible tumour suppressor genes. Combining these comparisons, together with known gene functional data, allowed the identification of eleven potential tumour suppressor genes spread along 16q. It is proposed that breast cancers with a single copy of 16q results in the simultaneous reduction of expression of several tumour suppressor genes. The existence of multiple tumour suppressor genes on 16q would severely limit any attempt to pinpoint tumour suppressor genes locations based on localised hot-spots of loss of heterozygosity. Interestingly, the majority of the identified tumour suppressor genes are involved in the modulation of wild-type p53 function. This role is supported by the finding that 80.5% of breast cancers with 16q loss have wild-type p53. TP53 is the most common mutated gene in cancer. In cancers with wild-type p53 would require other strategies to circumvent the key tumour suppressor role of p53. In breast cancers with complete loss of one dose of 16q it is suggested this provides a mechanism that contributes to the amelioration of p53 function.

scholarly journals Mutants of the tumour suppressor p53 L1 loop as second-site suppressors for restoring DNA binding to oncogenic p53 mutations: structural and biochemical insights

2010 ◽  
Vol 427 (2) ◽  
pp. 225-236 ◽  
Author(s):  
Assia Merabet ◽  
Hellen Houlleberghs ◽  
Kate Maclagan ◽  
Ester Akanho ◽  
Tam T. T. Bui ◽  
...  
Keyword(s):  
Dna Binding ◽  
Double Mutant ◽  
Hot Spot ◽  
Binding Activity ◽  
Tumour Suppressor ◽  
Wild Type ◽  
Dna Binding Activity ◽  
Wild Type P53 ◽  
Dynamics Simulations ◽  
Tumour Suppressor P53

To assess the potential of mutations from the L1 loop of the tumour suppressor p53 as second-site suppressors, the effect of H115N and S116M on the p53 ‘hot spot’ mutations has been investigated using the double-mutant approach. The effects of these two mutants on the p53 hot spots in terms of thermal stability and DNA binding were evaluated. The results show that: (i) the p53 mutants H115N and S116M are thermally more stable than wild-type p53; (ii) H115N but not S116M is capable of rescuing the DNA binding of one of the most frequent p53 mutants in cancer, R248Q, as shown by binding of R248Q/H115N to gadd45 (the promoter of a gene involved in cell-cycle arrest); (iii) the double mutant R248Q/H115N is more stable than wild-type p53; (iv) the effect of H115N as a second-site suppressor to restore DNA-binding activity is specific to R248Q, but not to R248W; (v) molecular-dynamics simulations indicate that R248Q/H115N has a conformation similar to wild-type p53, which is distinct from that of R248Q. These findings could be exploited in designing strategies for cancer therapy to identify molecules that could mimic the effect of H115N in restoring function to oncogenic p53 mutants.

scholarly journals An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Thao Thi Thanh Nguyen ◽  
Masato Shingyoji ◽  
Michiko Hanazono ◽  
Boya Zhong ◽  
Takao Morinaga ◽  
...  
Keyword(s):  
Wild Type ◽  
Inhibitory Effects ◽  
Cytotoxic Effects ◽  
P53 Expression ◽  
Nuclear Factor I ◽  
Infected Cells ◽  
Wild Type P53 ◽  
Mdm2 Inhibitor ◽  
P16 Expression

AbstractA majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

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