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Results for “Genes, p53”

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PubMed1990

Protein-binding elements in the promoter region of the mouse p53 gene.

p53 is a cellular protein whose expression plays a crucial role in the regulation of cell proliferation and of neoplastic processes. p53 mRNA levels in mouse fibroblasts can be elevated in response to TPA and to serum stimulation. The promoter region of the p53 gene contains a conserved element which is highly homologous to the consensus AP1 binding site (7/8 matching bases). This AP1-like site, denoted the PF1 site, confers upon a heterologous promoter ability to respond to elevated expression of c-jun. Furthermore, the PF1 site binds protein(s) in a specific and serum-induced manner. Unexpectedly, this factor is most probably not AP1, as evident from the inability of an authentic AP1 site to compete the binding efficiently, as well as from the failure of purified AP1 to bind to the PF1 site. Hence, PF1 may be a novel AP1-related transcription factor. In addition, the 5' region of the p53 gene also contains an NF1 binding site, whose location suggests a possible regulatory role.

Animals↗

PubMed1995

p53 gene mutations, p53 protein accumulation and compartmentalization in colorectal adenocarcinoma.

p53 accumulation may occur in the nucleus and/or cytoplasm of neoplastic cells. Cytoplasmic accumulation has been reported to be an unfavorable, but not established, prognostic indicator in colorectal cancer. Different types of p53 intracellular compartmentalization could depend either on p53 gene mutations or on the interaction with p53 protein ligands. The purposes of our study were (1) to assess whether the different patterns of p53 accumulation are selectively associated with p53 mutations and (2) to evaluate the clinical significance of p53 mutations in colorectal carcinomas. We evaluated p53 gene mutations in colorectal carcinomas. We evaluated p53 gene mutations in exons 5 through 8, by polymerase chain reaction and single-strand conformation polymorphism analysis; p53 accumulation and intracellular compartmentalization were detected immunocytochemically with the antibodies PAb1801 and CM1. p53 mutations were found in 74 of 126 carcinomas (59%). Nuclear p53PAb1801 accumulation was associated with p53 gene mutations (P < 0.001) whereas cytoplasmic p53 CM1 accumulation was more likely to occur with the wild-type p53 gene (P = 0.048). Overall, 112 carcinomas (89%) displayed p53 gene mutations and/or p53 accumulations of any type. p53 mutations were not correlated with important clinicopathological parameters and were not related to patient survival. Our data suggest that mechanisms other than mutations may also play a role in inhibiting p53 tumor-suppressing functions in colorectal carcinomas. Cytoplasmic p53CM1 accumulation frequently does not depend on p53 mutations.

Adenocarcinoma↗

PubMed1994

Aberrations of the tumor suppressor p53 gene and p53 protein in solar keratosis in human skin.

Aberrations of the p53 gene in 27 solar keratoses were examined by the polymerase chain reaction and single-strand conformation polymorphism and DNA sequencing analyses. In a series of Japanese patients, eight of 27 cases (30%) of solar keratosis showed structural abnormalities of the p53 gene. Six of eight aberrations of p53 gene were determined to be single nucleotide substitutions, and five of these were located at a dipyrimidine site. In solar keratosis, noticeable mutations were C to T in three cases, and one each of C to A and T to C nucleotide changes. p53 protein was detected immunohistochemically in the nuclei of six of 27 cases (22%) of solar keratosis. Nuclear staining for p53 protein was only significantly correlated with the presence of missense mutation of p53 gene (p < 0.01). Aberrations of the p53 gene in solar keratosis may be a marker to predict early cancerous lesions.

Base Sequence↗

PubMed1996

p16/CDKN2 gene and p53 gene alterations in Japanese non-smoking female lung adenocarcinoma.

Primary lung adenocarcinomas in non-smoking females are increasing in the USA and Japan. Environmental factors such as passive smoking, asbestos, domestic radon, and hormonal effects have been implicated, but the etiology is still uncertain. We therefore analyzed point mutations of p16 gene, a newly characterized tumor suppressor gene, and compared the results with alterations of p53 gene in 28 primary lung adenocarcinomas in non-smoking Japanese females. There were no cases with somatic point mutation of p16 gene, except for one case with two germline mutations (silent mutations). In contrast, six out of 16 informative cases showed loss of heterozygosity of p53 gene using a TP53 microsatellite marker and 19 out of 28 cases showed expression of oncoprotein using DO-7 immunohistochemistry. These findings suggest that p16 gene alteration is a rare event in primary lung adenocarcinomas in Japanese non-smoking females, compared with alterations of the p53 gene.

Adenocarcinoma↗

PubMedDate not supplied

Correlation between p53 gene mutation, p53 protein labeling and PCNA expression in oral squamous cell carcinomas.

BACKGROUND: The prevalence of oral squamous cell carcinoma (OSCC) among the Black community in South Africa is unacceptably high. The association between p53 protein, and PCNA overexpression and the presence of p53 gene mutations was evaluated. MATERIALS AND METHODS: One hundred and ten formalin-fixed, paraffin-embedded blocks of OSCC were selected for immunohistochemical studies for p53 protein and PCNA expression using the DO-7 and PC10 monoclonal antibodies, respectively. DNA was extracted from fifty-five blocks and exons 5 to 9 of the p53 gene were amplified with nested primers, thereafter sequencing was performed to confirm the presence of mutations detected by single stranded conformational polymorphism. RESULTS: Fifty-six cases (51%) showed p53 expression, while fourteen mutations (25%) were detected. A significant difference was found between the PCNA index in p53 positive and p53 negative tumors while the mean PCNA index for the tumors with p53 mutations was not significantly different from the tumors without mutations. CONCLUSIONS: No association between p53 protein overexpression and p53 gene mutations could be demonstrated.

Adult↗

PubMed1991

Loss of heterozygosity of p53 gene and p53 protein expression in human colorectal carcinomas.

The p53 gene is a tumor suppressor gene located on chromosome 17p. Deletions of this chromosome and point mutations of p53 have been implicated in the development of colonic neoplasms. We have analyzed the loss of heterozygosity of the human p53 tumor suppressor gene in 40 cases of colorectal carcinoma using two restriction fragment length polymorphisms detected by BglII and AccII restriction enzymes. p53 gene product expression was studied immunohistochemically in 64 colorectal carcinomas, 18 adenomas, and 40 normal colonic mucosae using an anti-human p53 monoclonal antibody (Pab 1801) and the avidin-biotin-peroxidase complex technique. Twelve of the 40 patients (30%) were polymorphic for the p53 gene. In ten of these informative patients (83%), the tumor samples showed the loss of one allele when compared with normal colorectal samples of the same patient. One of the homozygous patients showed a loss of both p53 alleles. p53 immunostaining was observed in 43 of 64 carcinomas (67%) but only in two adenomas (11%). These two positive adenomas showed areas of carcinoma in situ. The normal mucosa was always negative. No relation could be found between p53 immunostaining and the degree of differentiation, the extension of the tumor, or the Ki-67 proliferative index. Mucinous carcinomas and right-side carcinomas were less p53 immunoreactive (25% and 52%, respectively) than the usual adenocarcinomas (73%) and distal tumors (72%). These findings suggest that p53 may be a target of chromosome 17 deletions and that this gene may play a role in the malignant transformation of adenomas. BglII and AccII restriction fragment length polymorphism analysis of the p53 gene may be a useful and direct technique to detect allelic loss of this gene in tumors.

Adenocarcinoma↗

PubMed2003

Expression of p53 gene in stage IIIA non-small cell lung cancer in patients after neoadjuvant chemotherapy with Vepesid and Cisplatin.

Apoptosis (programmed cell death) plays a very important role in the development regulation, homeostasis maintenance as well as in the origin of many diseases, including neoplasms. This process is genetically regulated and reflected in characteristic morphological and biochemical changes taking place in cells. The process is considered to be of great significance in tumour originating and growth as well as in tumour cell response to chemotherapy. There are many genes and their products that are involved in apoptosis. The following genes: p53, bcl-2 and p21 seem to have the greatest significance. Our study aimed at evaluating p53 gene expression in non-small-cell lung cancer patients after neoadjuvant chemotherapy. We examined the tissue material from 35 patients after three-cycle inductive chemotherapy (Vepesid and Cisplatin). The material was obtained before chemotherapy during bronchofiberoscopy and four weeks after drug treatment during surgery. The control group comprised patients who had not undergone inductive chemotherapy. After deparaffinising of tissue slides, gene p53 activity using in situ hybridisation technique was evaluated. Moreover, apoptosis valuation with TUNEL method was performed. The results were documented as photographs. Gene p53 activity level was estimated using cytophotometric technique. Our study revealed significantly higher percentage of cells undergoing apoptosis and increased gene p53 activity in tumour tissue slides of patients after neoadjuvant chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Correlations between intrinsic chemoresistance and HER-2/neu gene expression, p53 gene mutations, and cell proliferation characteristics in non-small cell lung cancer cell lines.

Using a panel of 20 non-small cell lung cancer (NSCLC) cell lines established from previously untreated patients, we investigated the relationships between intrinsic chemoresistance (to four agents used commonly in the therapy of NSCLC) and HER-2/neu gene expression (which encodes glycoprotein p185neu), p53 gene mutations, and cell proliferation characteristics. Our results demonstrated that high p185neu expression was correlated with chemoresistance, low S-phase fractions, and long doubling times. By contrast, cell lines expressing relatively low levels of p185neu were relatively chemosensitive and had higher S-phase fractions and shorter doubling times. Although mutation of the p53 gene was a common event in this panel of cell lines (present in 18 of 20 lines), there was no relationship between mutations at any specific codon and chemoresistance or cell proliferation characteristics. Multivariate analysis revealed that the level of p185neu was the only independent predictor for chemoresistance to doxorubicin, etoposide, and probably cisplatin. Although intrinsic chemoresistance almost certainly is a multifactorial process, overexpression of p185neu may be an important factor in the chemoresistance of NSCLC.

Carcinoma, Non-Small-Cell Lung↗

PubMed1994

Relative efficiency of denaturing gradient gel electrophoresis and single strand conformation polymorphism in the detection of mutations in exons 5 to 8 of the p53 gene.

p53 is the most commonly mutated gene in a large variety of human tumors including familial cancers. Because p53 mutations have in a number of human cancer types, been related to a negative outcome of the disease and the importance of pre-symptomatic diagnosis in cancer-prone families, screening for p53 mutations is becoming more and more widely used. In order to avoid sequencing of the complete coding sequence, several pre-screening methods have been developed and applied to the p53 gene. Among them, Single Strand Conformation Polymorphism (SSCP) and Denaturing Gradient Gel Electrophoresis (DGGE) appear to be highly sensitive. In this work, we used 52 different p53 variants to compare the two methods. In our conditions, DGGE is more sensitive than SSCP since 100% of the variants were detected. SSCP detected 90% of the variants, but efficiency of the method can still be improved by additional optimization experiments.

Base Sequence↗

PubMed2002

[Inhibition of K562 cell proliferation by wild type p16 and p53 genes co-transfection].

The tumor suppressor gene p53 and p16, both of which play an important role in inhibition of tumorigenesis, are homozygously deleted in human myeloid leukemia cell line K562. To explore the inhibition of K562 cell proliferation by wild type p16 and p53 genes, both p16 and p53 genes were co-transfected into K562 cells mediated by liposome. The expression of the two genes was measured by immunocytochemical method, the cell cycle was analysed by flow cytometry, and the number of recovered viable cells was assessed after transfection. After co-transfection, the p53 and p16 positive cells were 23% and 28%, respectively. The results showed that co-transfection of p16 and p53 genes significantly inhibits cell proliferation comparing with transfection either by p16 gene or by p53 gene (P < 0.05). Expression of p16 and p53 proteins increased the cell number in G(1) phase but decreased the cell number in S phase. It is concluded that co-transfection of p16 and p53 genes has a stronger growth-inhibitory effect on K562 cell growth than that of transfection only by p16 gene or by p53 gene, may be a pathway for gene therapy in leukemia.

Cell Division↗

PubMed1998

Clinical implication of screening p53 gene mutations in head and neck squamous cell carcinomas.

The role of the tumour-suppressor gene p53 in the tumorigenesis of head and neck cancer has been well established, but the clinical significance of p53 alteration is still unclear. A group of 50 patients with head and neck squamous cell carcinoma (HNSCC) were investigated for p53 alterations. DNA was extracted from fresh tumour samples and polymerase chain reaction/single-strand conformation polymorphism analysis was used to detect p53 gene mutations in the region from exon 5 to exon 9. In addition, p53 protein overexpression was assessed by immunohistochemistry using the monoclonal antibody DO-7 on paraffin-embedded tissue sections. p53 gene mutations were found in 45% and p53 protein expression was detected in 61.2% of tumour samples. While p53 protein expression was not correlated with any clinical factors, p53 gene mutations indicated local regional recurrences of HNSCC. The risk of locoregional recurrence was significantly greater in patients with a p53 gene mutation than in patients with the wild-type p53 gene (P = 0.001). Multivariate analysis confirmed p53 gene mutation to be an independently predictive factor for the tumour recurrence (P = 0.0064). When we analysed p53 gene mutation in 12 patients with primary and recurrent tumours, we found that 4 patients (33.3%) had a different p53 gene mutation in the recurrent tumour from that in the original primary tumour. The results indicate that p53 gene mutations and not protein overexpression are valuable predictors for tumour recurrences and for differential diagnosis of a second primary HNSCC.

Biomarkers, Tumor↗

PubMed1994

3-Methylcholanthrene inactivates the p53 gene in Syrian hamster embryo fibroblasts by inducing a specific intronic point mutation.

The expression of the tumor suppressor gene p53 was studied in Syrian hamster embryo cells neoplastically initiated with a single dose of 3-methylcholanthrene. Ten randomly selected individual 3-methylcholanthrene-transformed colonies were established in culture independently. Eight of these cell lines contained levels of p53 mRNA similar to those in primary embryo cells (p53+ cell lines), as measured by Northern blot analysis of total RNA, whereas two of them (81C43 and 81C47) showed no detectable levels of p53 mRNA (p53- cell lines). However, Southern blot and karyotype analyses did not reveal any significant changes in copy number or gross rearrangements of the p53 gene in any of the p53- cell lines. A 3-kilobase genomic fragment cloned from p53- cells (81C47) containing both upstream and downstream promoters of the p53 gene was able to drive the expression of a CAT reporter gene when transfected into either p53+ or p53- cells. Furthermore, run-on assays performed on nuclei of p53- cells showed that the p53 gene was transcriptionally active, demonstrating that the genetic defect leading to the lack of p53 expression was not due to alterations in the promoter region. Detection of mRNA species corresponding to p53 mRNA precursors in Northern blot analysis of polyadenylated RNA from both p53+ and p53- cells indicated that the lack of p53 expression was not caused by mutations in the 3' regulatory region of the p53 gene affecting transcription termination and/or polyadenylation of p53 precursor mRNA. PCR amplification and nucleotide sequence analysis of extensive internal regions of the gene revealed that both p53- cell lines were homozygous for the same unique point mutation on the splice acceptor site of the fifth intron, a G to C transversion in the last nucleotide of the intron. The presence of this mutation in both p53- cell lines strongly suggests that it was induced specifically by 3-methyl-cholanthrene treatment and indicates that the resulting splicing malfunction may account for the lack of p53 gene expression.

Animals↗

PubMed1997

[A study on the significance of p53 gene mutation, P53 protein positive staining and PCNA staining].

After obtaining the results of p53 gene mutation by a silver staining method to polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, P53 protein staining and proliferation cell nuclear antigen (PCNA) index by double-blind method, multivariate correlation analysis two by two showed that PCR-SSCP, P53 positive protein staining and PCNA index had markedly correlation not only in oral precancerous lesions (OPL) but also in primary sites and regional metastatic lymph nodes of oral squamous cell carcinomas (OSCC). This indicated that the nature of the three indexes was the same. After introducing the sex and age of patients which have been proved to be related to the initiation and development of OPL and OSCC according to other researchers and are easy to be obtained in clinics, multivariate discriminatory analysis was carried on and three groups of discriminatory equations were gotten about the pathological grading of OPL and OSCC and metastasis condition of OSCC. The accuracy of these equations was 82.5%, 78% and 80%, individually. This suggests that the equations have applicable potentiality already.

Carcinoma, Squamous Cell↗

PubMed2002

Co-transfection of p16(INK4a) and p53 genes into the K562 cell line inhibits cell proliferation.

BACKGROUND AND OBJECTIVES: The tumor suppressor genes p53 and p16(INK4a), both of which act in tumor surveillance, are homozygously deleted in the human leukemia cell line K562. This study was performed to assess whether co-transfection of the p16(INK4a) and p53 genes could inhibit K562 cell proliferation. DESIGN AND METHODS: p16(INK4a) and p53 genes were co-transfected into K562 cells with liposome, and the expression of the transfected genes was detected by Western-immunoblotting and immunocytochemistry. The effect of the p16(INK4a) and p53 transfected cell culture was quantified by trypan blue staining, and the number of recovered viable cells was assessed every day after transfection. Cells were analyzed for expression of annexin V in order to detect apoptosis. Differentiation of transfected K562 cells was measured by the benzidine oxidation test, and the cell cycle was analyzed by flow cytometry. RESULTS: After co-transfection, there were 23% and 28% p53 and p16(INK4a) positive cells respectively. Co-transfection with p16(INK4a) and p53 genes significantly inhibited cell proliferation when compared to transfection with either p16(INK4a) or p53 gene. The percentage of cells expressing the apoptosis-related cell surface antigen annexin V was significantly higher in p53 and p16(INK4a) transfected cells than in p53 or p16(INK4a) transfected cells (6.24+/-0.37% vs 4.88+/- 0.17%, p<0.05 and vs 2.78+/-0.26%, p<0.05, respectively). p16(INK4a) and p53 co-transfection significantly increased the number of cells in G1 phase and decreased that in S phase. INTERPRETATION AND CONCLUSIONS: Expression of wild-type p16(INK4a) and p53 genes in K562 cells results in reduced proliferation and apoptosis. Introduction of exogenous p16(INK4a) and p53 genes into K562 cells might contribute to the clinical treatment of leukemia.

Annexin A5↗

PubMed2003

VEGF expression and its reguration by p53 gene transfection in endometrial carcinoma cells.

Vascular endothelial growth factor (VEGF) that activates endothelial cell growth induces angiogenesis, which is indispensable to tumor igenesis and tumor progression. On the other hand, tumor suppressor gene p53 has been considered to regulate VEGF expression, but the detailed relationship between them remains unclear. In this study, we aimed to study VEGF expression in endometrial carcinoma cells and the effect of p53 gene transfection on VEGF expression using p53-mutated endometrial carcinoma cell line, HEC-50B. Immunoblotting for detecting VEGF protein, p53 protein and beta-actin was performed using 11 endometrial carcinoma cell lines. Levels of VEGF in the cultured media were measured by Enzyme immunoassay(EIA). Transfection of wild p53 gene was carried out by SuperFect method in HEC-50B cells, which had mutant p53 gene and did not express p53 protein. The results of immunoblotting were analyzed by NIH image and expressed as values. The results of EIA were expressed as the relative value. The VEGF value was 0.8 +/- 0.3 (n = 6) in p53-wild group, whereas in p53-mutant group it was 1.6 +/- 0.8 (n = 5). VEGF expression was correlated significantly with p53 status (P < 0.05). VEGF levels in p53 gene-transfected cells and the conditioned medium were decreased in 48 hours after p53 gene transfection. VEGF expression was down-regulated by p53 in endometrial carcinoma cells.

Cell Line, Tumor↗

PubMed1994

Alteration of p53 gene in ovarian carcinoma: clinicopathological correlation and prognostic significance.

Inactivation of the tumour-suppressor gene p53 has been demonstrated in a variety of human tumours. We extracted DNA from paraffin-embedded tissues of 67 ovarian carcinoma samples (54 primary tumours, seven metastases and six tumours obtained after chemotherapy), and analysed allelic losses and mutations of the p53 gene using single-strand conformation polymorphism (SSCP) analysis of DNA fragments amplified by a polymerase chain reaction (PCR). Allelic loss was observed in 24 of 32 informative cases. The mutation was detected in 14 of 54 primary ovarian carcinomas: eight serous cystadenocarcinomas (SCA), 42%), five endometrioid adenocarcinomas (EA, 42%) and one mucinous cystadenocarcinoma (14%). The incidence of the alteration was higher in SCA and EA than in other histological types, but the difference was not statistically significant. The incidence of p53 gene abnormalities in ovarian carcinomas tended to be increased in patients with disease advanced (over FIGO stage II). Mutations were found in exons 5 and 7 only and consisted mainly of single nucleotide substitutions [9 or 14 (64%) in exon 7; 4 of 14 (29%) in exon 5]. In 13 of 14 cases, p53 gene mutations occurred concomitantly with losses of the normal allele. The status of the p53 gene in metastases and the tumours obtained after chemotherapy was identical to that in the primary tumours. The presence of p53 gene mutation did not correlate with histological grade, response to primary therapy and survival. These findings suggest that mutational alterations of the p53 gene are involved in the development of a significant proportion of some ovarian carcinomas (SCAs or EAs), especially in advanced stages. However, they may not be a marker predicting the biological behaviour or the outcome of the disease.

Adenocarcinoma, Clear Cell↗

PubMed1995

Mutations of the p53 gene and p53 protein overexpression are associated with sarcomatoid transformation in renal cell carcinomas.

Renal cell carcinomas sometimes show sarcomatoid transformation, thus comprising both sarcomatous and carcinomatous components. Such sarcomatoid renal cell carcinomas are highly malignant with pronounced proliferative activity. The present investigation was conducted to assess the mutational status of the p53 and H-ras genes independently in carcinomatous and sarcomatous portions of individual tumors, applying PCR, subcloning, and sequencing to 14 cases. Sarcomatoid portions showed an extremely high mutation rate for the 53 gene (11 of 14, 78.6%) with two mutational hot spots at codons 278 (8 of 14, 57.1%) and 244 (6 of 14, 42.9%). Five cases showed double mutations, four cases had mutations at codons 278 and 244, and one case had mutations at codons 278 and 248. In contrast, the carcinomatous portions demonstrated a low mutation rate for the p53 gene (2 of 14, 14.3%) and no double mutations were detected. Ten cases showed genetic heterogeneity in the p53 gene between the two tumor components. Furthermore, p53 overexpression was immunohistochemically observed only in those components with p53 mutations, mainly in the sarcomatoid portions. No H-ras mutations were observed. The findings strongly suggest that p53 mutations leading to overexpression of p53 protein are closely associated with sarcomatoid transformation in renal cell carcinomas.

Amino Acid Sequence↗

PubMed1995

Analysis of the p53 gene in human choriocarcinoma cell lines.

In the present study, we analysed human choriocarcinoma cell lines for abnormalities in the tumour-suppressor gene p53 by Southern blotting, Northern blotting, non-radioisotopic single-stranded conformational polymorphism (SSCP) and complementary DNA sequencing. In all cell lines (Bewo, GCH-1, GCH-2, SCH, JAR, JEG-3, NUC-1 and HCCM-5), no p53 gene abnormality was detected by using Southern blotting. p53 mRNA of the expected size was detected in all cell lines tested by Northern blotting. SSCP analysis revealed abnormalities of p53 cDNA in the SCH cell line. Sequencing analysis of the entire coding region of the p53 gene revealed that both alleles were expressed in the JEG-3 cell line, and one of the alleles contained a point mutation (G to T) in codon 167 (Gln to His). In the NUC-1 cell line both alleles were point mutated. One allele had a point mutation (A to T) that resulted in a codon 17 change (Glu to Asp), and another had a point mutation (A to T) that caused a codon 24 change (Lys to Asn). In the SCH cell line, AGG was inserted between codon 249 and 250; this insertion resulted in an abnormal structure of the p53 protein. In three out of eight human choriocarcinoma cell lines, a p53 gene abnormality was detected. Therefore our data demonstrate that p53 gene abnormalities are associated with choriocarcinoma cell lines.

Base Sequence↗