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Results for “mutant p53”

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At least 19 recordsLinked to original sources

PubMed1992

Expression of mutant p53 proteins in lung cancer correlates with the class of p53 gene mutation.

We investigated the immunocytochemical staining and immunoblotting characteristics of 33 different p53 mutant proteins identified in lung cancer cell lines (18 small-cell lung cancer and 15 non-small-cell lung cancer) using monoclonal antibodies pAbs 240, 421 and 1801. The p53 mutants studied were representative of those found in lung cancer and included three deletions, four nonsense, seven splicing and 19 missense lesions. Control cell lines included six B-lymphoblastoid cell lines and two lung cancer cell lines without p53 mutations. Immunocytochemistry demonstrated 16 cell lines (48%) with definite overexpression of p53 protein (the high-expresser group of mutants), while in the remainder of cases either no p53 expression or low levels of p53 protein expression were found (the low-expresser group of mutants). The type of p53 mutation correlated with the expresser group. High expressers all had p53 missense mutations in exons 5-8, and immunocytochemistry identified 16/17 (94%) of these mutants. Several classes of p53 mutations occur in the low-expresser groups: deletions, splicing mutants, nonsense mutants and missense mutations outside of exons 5-8 all resulted in very low or undetectable levels of p53 protein. We conclude that there are low- and high-expression groups of p53 mutants in lung cancer and that the detection of protein expression in tumor cells by immunocytochemistry and immunoblotting is dependent upon the type of mutation of the p53 tumor-suppressor gene.

Blotting, Western↗

PubMed1992

p53 gene mutations in human gastric cancer: wild-type p53 but not mutant p53 suppresses growth of human gastric cancer cells.

To further investigate the role of p53 gene inactivation in gastric tumorigenesis, the mutational status of the p53 gene in primary human gastric cancer samples was examined. Reverse transcriptase polymerase chain reaction and subsequent direct sequencing of the p53 gene from gastric cancer samples revealed frequent point mutations of the p53 gene: some of these coincided with those previously identified in gastric cancer cell lines. In addition, both allelic deletion analysis using pYNZ 22 and polymerase chain reaction-restriction fragment length polymorphism analysis demonstrated an allelic deletion of the p53 gene in cancer tissue which contained a point mutation of the p53 gene in the remaining allele. Transfection of the wild-type or mutant p53 genes into gastric cancer cells showed that the wild-type but none of the mutated p53 genes suppressed the colony formation of gastric cancer cells. Furthermore, the incorporation of thymidine into DNA was reduced in cancer cells expressing the wild-type p53 gene. The glutathione S-transferase-wild type p53 fusion protein bound to simian virus 40 large T antigen in COS-1 cell lysate. None of the p53 fusion proteins containing mutations at codons 143, 175, 248, or 273 bound to simian virus 40 large T antigen. By contrast, two different mutant p53 fusion proteins containing mutations specifically observed in gastric cancer bound to simian virus 40 large T antigen. These results indicate that inactivation of the p53 gene through mutations and the allelic deletion may play an important role in gastric tumorigenesis. These mutations may cause a conformational change in the p53 protein resulting in the loss of the suppression by p53 of the growth of gastric cells, partly through disruption of the association of p53 protein with a cellular component.

Antigens, Viral, Tumor↗

PubMed1992

A mutant p53 protein is required for maintenance of the transformed phenotype in cells transformed with p53 plus ras cDNAs.

Mutant p53 and activated ras cDNA clones cooperate to fully transform primary rat embryo fibroblasts in cell culture, whereas neither cDNA alone results in the full transformation of these cells. The mutant p53 protein may be required to initiate the transformation event with ras. Alternatively, mutant p53 gene expression may be required to maintain the properties of the transformed phenotype. To distinguish between these possibilities, primary rat embryo fibroblasts were transformed with mutant p53 plus ras cDNAs, where the expression of the p53 gene was regulated by an isopropyl beta-D-thiogalactoside-responsive promoter. When expression of the mutant p53 cDNA was inhibited and no detectable exogenous p53 protein was produced, both the growth rate and the morphology of the cells reverted to a normal phenotype. These results demonstrate that a mutant p53 protein is required for the maintenance of the transformed phenotype in cells transformed with p53 plus ras cDNAs.

Animals↗

PubMed1992

Site-specific binding of wild-type p53 to cellular DNA is inhibited by SV40 T antigen and mutant p53.

Wild-type p53 protein was shown to bind specifically to DNA sequences within SV40 (Bargonetti et al. 1991), the human ribosomal gene cluster (RGC) (Kern et al. 1991a), and the murine muscle creatine kinase gene (MCK) (Zambetti et al. 1992). However, a direct comparison of these three sites was not performed. Here we demonstrate, by filter binding and gel mobility-shift assays, that wild-type p53 binds with similar affinities to MCK and RGC sites but less tightly to the SV40 site. We examined the effects of two candidate regulators of p53 function, SV40 large T antigen and oncogenic mutant p53, on the binding of wild-type p53 to RGC DNA. We show that wild-type T antigen prevents p53 from binding to the RGC site under all conditions tested. Moreover, two temperature-sensitive mutant SV40 T antigens, which fail to transform cells at the nonpermissive temperature, prevent p53 from binding to the RGC site at the permissive, but not at the restrictive, temperature. The ability of complexes containing wild-type p53 and tumor-derived mutant p53 proteins to bind to RGC DNA varies according to the position of the mutation. Complexes containing wild-type and either his175 or his273 mutant p53 proteins are completely unable to bind to the RGC DNA sequence. Interestingly, a complex containing wild-type p53 and the trp248 mutant p53 characteristic of Li-Fraumeni syndrome patients displays nearly wild-type levels of binding. Perhaps this mutant allele can be tolerated in these individuals because the wild-type mutant p53 complex maintains the ability to bind to DNA. Our data indicate that the oncogenic potential of both T antigen and some mutant p53 proteins is the result of their ability to block binding of wild-type p53 to DNA.

Animals↗

PubMed1992

Mutant p53 expression in solar keratosis: an immunohistochemical study.

Thirty-eight solar keratoses from 32 patients were studied for expression of mutant p53 protein by an immunohistochemical technique. Twenty-eight of the 38 solar keratoses (73.7%) showed positive and variable nuclear labelling, whereas 10 specimens were immunonegative. The nuclear immunopositivity which was seen in all variants was mostly diffuse in distribution. The adjacent "normal" epidermis of 8 keratoses showed positive mutant p53 labelling. Eight of the keratoses were associated with invasive squamous cell carcinoma of which only two were immunopositive. Cytoplasmic labelling was never a feature. The study demonstrates that mutant p53 protein is commonly expressed in all variants of solar keratosis and that its expression correlates with atypical keratinocyte proliferation. It is proposed that the demonstration of mutant p53 in the adjacent normal epidermis may be a potential marker of early neoplastic transformation.

Aged↗

PubMed1992

Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles.

Loss of cell cycle control and acquisition of chromosomal rearrangements such as gene amplification often occur during tumor progression, suggesting that they may be correlated. We show here that the wild-type p53 allele is lost when fibroblasts from patients with the Li-Fraumeni syndrome (LFS) are passaged in vitro. Normal and LFS cells containing wild-type p53 arrested in G1 when challenged with the uridine biosynthesis inhibitor PALA and did not undergo PALA-selected gene amplification. The converse occurred in cells lacking wild-type p53 expression. Expression of wild-type p53 in transformants of immortal and tumor cells containing mutant p53 alleles restored G1 control and reduced the frequency of gene amplification to undetectable levels. These studies reveal that p53 contributes to a metabolically regulated G1 check-point, and they provide a model for understanding how abnormal cell cycle progression leads to the genetic rearrangements involved in tumor progression.

Aspartic Acid↗

PubMed2026

SLC25A45 as a prognostic biomarker promotes malignant progression via mutant p53 in hepatocellular carcinoma.

BACKGROUND: SLC25A45 belongs to the mitochondrial trimethyllysine carrier protein family. To date, its role in tumor development has not been fully elucidated. Previous studies have demonstrated its pro-tumor function in ovarian cancer; however, research on the expression characteristics, biological roles and underlying regulatory pathways of SLC25A45 in hepatocellular carcinoma (HCC) is limited. This study aims to explore the expression, functional roles, and regulatory pathways of SLC25A45 in HCC. METHODS: This study examined SLC25A45 expression and clinical relevance in HCC using publicly available transcriptomic data. SLC25A45 knockdown cell lines were constructed using PLC/PRF/5, Huh7, and Huh1 cells. Functional assays, including cell proliferation and colony formation assays, were then conducted. To investigate the effects of SLC25A45 knockdown on the malignant phenotypes of HCC cells in vitro, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) analyses were performed to identify potential underlying mechanisms, which were subsequently validated by experimental assays. RESULTS: SLC25A45 was elevated in clinical HCC specimens, and high SLC25A45 expression was correlated with disease progression and poor overall survival (OS). In vitro functional assays demonstrated that SLC25A45 silencing reduced HCC cell proliferation and colony formation. Mechanistically, GSEA indicated that high SLC25A45 expression was significantly enriched in the p53 signaling pathways. SLC25A45 knockdown in HCC cells led to a significant increase in wild-type p53 protein expression, but a substantial decrease in mutant p53 expression. CONCLUSIONS: SLC25A45 is a potential prognostic indicator and may drive HCC tumorigenesis and progression through the differential modulation of the p53 signaling pathways.

SLC25A45↗

PubMed1992

Mutant p53 protein is expressed in Bowen's disease.

A total of 26 specimens of histologically determined, cutaneous Bowen's disease from 23 patients were investigated for the incidence of mutant p53 protein expression by an indirect immunoperoxidase technique using the monoclonal antiserum CM1 on paraffin-embedded formalin-fixed tissue sections. Its potential role as a label of cutaneous malignancy was also evaluated: 15 specimens (57.7%) showed nuclear positivity of dysplastic keratinocytes, whereas 11 specimens (42.3%) were immunonegative. Cytoplasmic labeling was never a feature. In general, labeling was predominantly diffuse in distribution although in a significant proportion it was focal. One of two concurrent basal cell carcinomas arising adjacent to plaques of Bowen's disease was immunopositive. Focal immunopositivity of "cytologically normal" adjacent epithelium was seen in six specimens (23%). The study confirms the presence of mutant p53 protein in the majority of nongenital Bowen's disease. Its identification within nuclei of the adjacent "normal" epidermis may represent a potential marker of early (visible) neoplastic transformation.

Aged↗

PubMed1992

Mutant p53 can substitute for human papillomavirus type 16 E6 in immortalization of human keratinocytes but does not have E6-associated trans-activation or transforming activity.

Human papillomavirus type 16 (HPV16) E6 and E7 are selectively retained and expressed in HPV16-associated human genital tumors. E6 is active in several cell culture assays, including transformation of NIH 3T3 cells, trans activation of the adenovirus E2 promoter, and cooperation with E7 to immortalize normal human keratinocytes. Biochemically, the HPV16 E6 protein has been shown to bind to tumor suppressor protein p53 in vitro and induce its degradation in a rabbit reticulocyte lysate. To examine the relationship between the various biological activities of E6 and inactivation of p53, we tested the abilities of dominant negative mutants of p53 to substitute functionally for E6 in the three cell culture assays. While wild-type p53 inhibited keratinocyte proliferation, both mouse and human mutant p53s, in conjunction with E7, increased proliferation of the keratinocytes, resulting in generation of immortalized lines. However, in contrast to E6, mutant p53 was unable to induce transformation or trans activate the adenovirus E2 promoter in NIH 3T3 cells. These results suggest that inactivation of wild-type p53 is necessary for HPV-induced immortalization of human keratinocytes and that different or additional activities are required for E6-dependent transformation and trans activation of NIH 3T3 cells.

3T3 Cells↗

PubMed1992

Diversity of human p53 mutants revealed by complex formation to SV40 T antigen.

The products of the two major suppressor genes p53 and Rb interact with the oncogene products of the DNA tumour viruses. These viral-host protein interactions mimic and interfere with the normal interactions of p53 and Rb with host proteins. The Rb gene product is frequently mutated in human cancers such that it no longer binds to viral or host proteins. In contrast we find that this is not the case with p53 as some, but not all, mutant p53 proteins still bind to the SV40 T antigen. In particular the hot spot mutation found in most Chinese and African cases of hepatocellular carcinoma (HCC) retains T binding activity. The simple subdivision of different p53 mutations revealed by this analysis may have diagnostic and prognostic consequences.

Antigen-Antibody Complex↗

PubMed1992

Loss of heterozygosity on chromosome 17p and mutant p53 in HPV-negative cervical carcinomas.

Inactivation of the protein product of the wild-type tumour suppressor gene p53 through complexing of the protein with the E6 oncoprotein of human papillomaviruses (HPV) in HPV-infected cells is thought to be important in the aetiology of cervical carcinoma. Mutations of p53 have also been reported in HPV-negative carcinomas, and we now demonstrate loss of heterozygosity (LOH) of chromosome region 17p13 (in which p53 is located) in such tumours. Immunocytochemical staining with monoclonal antimutant-p53 antibody revealed that the carcinomas with LOH on 17p and completely lacking HPV DNA sequences had mutant p53. Thus the LOH had apparently resulted in the loss of the wild-type allele. Consequently, in both HPV-positive and HPV-negative tumours there is loss of function of wild-type p53, in the former because the protein product of the p53 gene complexes with that of the viral E6 gene, in the latter because the protein is altered, presumably as a result of a direct alteration of the p53 gene but possibly because of other post-translational changes. That this mutant allele of the tumour suppressor gene may sometimes behave like an oncogene is suggested by the presence of more than the expected number of copies of the remaining chromosome 17 homologue in some carcinomas.

Chromosome Aberrations↗

PubMedDate not supplied

Mutant p53 product in patients with stage III cervical cancer.

Mutations in the p53 gene stimulate cell division. In our study we assessed the prognostic value of mutant p53 overexpression in cervical cancer stage FIGO III detected by immunohistochemistry. In 43 tissue specimens were detected p53 overexpression in 20 cases. Mean survival time was 36.4 (SE +/- 7.66) months in the p53 protein positive group. The group without p53 overexpression showed a mean survival time of 28.6 (SE +/- 3.85) months. p53 protein overexpression had no prognostic value in patients with stage III cervical cancer.

Female↗

PubMed2025

Mutant p53 disrupts antioxidant defense in fallopian tube epithelium via GSTAs suppression: A pathway to serous tubal carcinogenesis.

High grade serous ovarian cancer (HGSOC) is the most common and aggressive type of epithelial ovarian cancer. The fimbria of the fallopian tube is the likely site of origin based on the presence of distinct precancerous lesions with TP53 signatures known clinically as serous tubal intraepithelial carcinoma (STICs) detected in this region in individuals at genetically high risk or with HGSOC. Previously we identified that matched fallopian tube epithelia (FTE) from fimbria and ampulla of normal fallopian tubes from premenopausal women exhibit differential expression of genes associated with antioxidant and inflammatory pathways. One gene, glutathione S-transferase 2 (GSTA2), showed both higher expression in the fimbria and in the follicular phase (pre-ovulation) compared to the ampulla, suggesting that GSTA2 expression may regulate reactive oxygen homeostasis in these cells in response to ovulation-related stress. Here, to understand how preneoplastic genomic alterations influence regulation of oxidative stress, FTE cells were isolated from healthy tissue and introduced with p53 mutations, from which expression and function of GSTA2 and other antioxidant enzymes were investigated. Mutant p53 downregulated the expression of GSTA2 and subsequently increased DNA damage. The combination of p53 mutation and dysregulated oxidative response likely promotes the genomic instability that initially drives the transformation to high grade serous ovarian carcinoma.

Female↗

PubMed1992

Mutant p53 oncogene expression in keratoacanthoma and squamous cell carcinoma.

The tumour suppressor gene p53, located on the short arm of chromosome 17, encodes for a nuclear protein which regulates cell proliferation by inhibiting cells entering S-phase. p53 mutations are alleged to be the commonest genetic abnormality in human cancer. We studied mutant p53 oncoprotein expression, using PAb1801 monoclonal antibody immunohistochemistry, in 25 'ideal' keratoacanthomas and 26 well-, 19 moderately and 18 poorly differentiated squamous cell carcinomas of the skin. While there was a highly significant trend in the proportion of p53 oncoprotein-positive lesions from keratoacanthomas to poorly differentiated squamous cell carcinomas (chi 2 = 17.13, df = 1, exact P = 0.00003), p53 expression was inadequate for distinguishing keratoacanthoma from well-differentiated squamous cell carcinoma (chi 2 = 2.55, df = 1, exact P = 0.18; corresponding to a sensitivity of 0.84 and a specificity of only 0.36).

Carcinoma, Squamous Cell↗

PubMed1992

Expression of mutant p53 gene in squamous carcinoma arising in patients with recessive dystrophic epidermolysis bullosa.

Epidermolysis bullosa, a rare genodermatosis, is characterized by increased skin fragility manifest as blistering and sometimes accompanied by scarring. The latter is particularly severe in the recessive dystrophic variant and may be complicated by the development of squamous carcinoma in up to 30% of patients. We have studied 23 such tumours in six patients with this variant, with an anti-serum to p53 protein. Twenty-six per cent of the squamous carcinomas labelled positively for mutant-type p53 protein. This low figure, however, reflects the large number of well-differentiated tumours in this series, where 14 out of 15 were negative. In the moderate to poorly differentiated examples the positivity rate was 63%. Of the three patients in the latter category, one has died from disseminated tumour and another has widespread metastases. The findings support the hypothesis that mutant p53 protein expression correlates with poorer tumour differentiation. They also suggest a possible correlation between p53 protein expression and tumour behaviour.

Carcinoma, Squamous Cell↗

PubMed1992

Growth inhibition by anchorage-deficiency is associated with increased level but reduced phosphorylation of mutant p53.

Human breast carcinoma MCF-7 cells seeded on type I collagen-coated dishes were provided with an anchor via the collagen receptor, integrin, and grew as actively as those in plastic tissue culture dishes. In contrast, cells seeded on a layer of soft agar became anchorage-deficient and their growth was significantly inhibited, although the cell viability and the cell cycle distribution were unaffected. Immunoprecipitation analysis revealed that mutant p53 was phosphorylated at tyrosine in the anchorage-provided cells. In contrast, the p53 in the anchorage-deficient cells was present in 2-fold greater amount, but was phosphorylated to a lesser extent. Addition of a potent protein-tyrosine kinase inhibitor, herbimycin A, to the anchorage-provided cells caused an elevated level of p53, and inhibitions of cell proliferation and p53 phosphorylation, without interfering with the cell adhesion to the substratum. These results demonstrated that the growth inhibition by anchorage-deficiency or by herbimycin A is associated with an elevated p53 level and reduced p53 phosphorylation at tyrosine.

Amino Acids↗

PubMed1992

Expression of p53 mutant nuclear phosphoprotein in oral carcinoma and potentially malignant oral lesions.

An immunohistochemical study of primary oral squamous cell carcinomas (n = 37) with a monoclonal antibody (PAb 1801) specific to p53 antioncogene product demonstrated nuclear overexpression of the mutant protein in 35% of cases. Those positive included carcinomas without deep invasion suggesting that p53 mutation may occur in the early stages of progression of a malignancy. This is supported by the observation that mutant protein was detectable in limited amounts in 2 cases of oral mucosal dysplasia (n = 12). None of the normal or reactive oral mucosal tissues (n = 17) were positive for p53. The presence or absence of p53 was not correlated with the site of the lesion or its degree of differentiation. Our data suggest that p53 gene mutations are commonly involved in oral cancer but are neither sufficient nor necessary for the development of malignancy. Nevertheless, as this mutation is the commonest genetic change described so far in cancers in white caucasoids, it is possible that its presence can be used as a marker of risk in a high proportion of malignant and potentially malignant oral lesions.

Carcinoma↗

PubMed1992

Mutant p53 can induce tumorigenic conversion of human bronchial epithelial cells and reduce their responsiveness to a negative growth factor, transforming growth factor beta 1.

Loss of normal functions and gain of oncogenic functions when the p53 tumor suppressor gene is mutated are considered critical events in the development of the majority of human cancers. Human bronchial epithelial cells (BEAS-2B) provide an in vitro model system to study growth, differentiation, and neoplastic transformation of progenitor cells of lung carcinoma. When wild-type (WT) or mutant (MT; codon 143Val-Ala) human p53 cDNA was transfected into nontumorigenic BEAS-2B cells, we observed that (i) transfected WT p53 suppresses and MT p53 enhances the colony-forming efficiency of these cells, (ii) MT p53 increases resistance to transforming growth factor beta 1, and (iii) clones of MT p53 transfected BEAS-2B cells are tumorigenic when inoculated into athymic nude mice. These results are consistent with the hypothesis that certain mutations in p53 may function in multistage lung carcinogenesis by reducing the responsiveness of bronchial epithelial cells to negative growth factors.

Animals↗