Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumour suppressor p53 gene serves as a critical regulator of the cell cycle and of apoptosis following the exposure of normal cells to DNA damage. To examine the role of p53 in postmitotic CNS neurons, we cultured cerebellar neurons from normal wild-type mice and mutant p53-null mice under various conditions inducing neuronal death. When cerebellar neurons from 15- to 16-day postnatal wild-type mice were treated with ionizing radiation or DNA-damaging agents, massive neuron death occurred after 24-72 h. In contrast, neurons from p53-/- mice evidently resisted gamma-irradiation and some DNA-damaging agents, such as etoposide and bleomycin. On the other hand, low-K+ medium-induced apoptosis of cerebellar neurons was not affected by p53 status. Neither cell cycle progression nor DNA synthesis occurred during cell death induced by gamma-irradiation and low-K+ medium, as well as in normal cultures of p53+/+ and p53-/- neurons. These results suggest that p53 is required for the apoptotic death of postmitotic cerebellar neurons induced by DNA strand breaks.
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PMID:Involvement of p53 in DNA strand break-induced apoptosis in postmitotic CNS neurons. 892 Dec 72

The tumour suppressor protein p53 is expressed at very low levels in normal cells but accumulates in response to DNA damaging agents such as u.v. irradiation. This increase is accompanied by transcriptional upregulation of the expression of a number of proteins including Mdm2 which can in turn inhibit p53 dependent transcriptional activation, creating a feedback loop resulting in down-regulation of p53 activity. Mutant p53 proteins are however frequently detected at constitutively high levels in many tumours and tumour cell lines, indeed this phenomenon has been used in several studies to diagnose p53 mutation in patient tumours. We show here that expression of mouse mutant p53 in tumour cell lines of this type results in high levels of both the endogenous p53 protein and the exogenously expressed mutant mouse protein, whereas the human tumour line MCF7 does not exhibit high levels of either endogenous human or exogenously expressed mouse mutant p53 unless stabilisation is induced by DNA damage. This suggests that the stability of mutant p53 is not intrinsic to mutant p53 protein structure but may vary in different cell backgrounds. We present evidence that p53 protein stability in tumour cell lines is determined by association with the Mdm2 tumour suppressor protein, and that p53 mutants which are unable to bind Mdm2 are stable in MCF7 cells. We propose that tumour lines which express high levels of transcriptionally inactive mutant p53 are unable to induce the expression of the Mdm2 protein which would normally provide a feedback mechanism down-regulating p53 protein levels in the absence of DNA damage signals. MCF7 cells however express a transcriptionally active p53 and retain the feedback regulation of p53 protein levels by Mdm2.
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PMID:p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding. 929 11

Bovine papillomavirus type 4 (BPV-4) does not possess an E6 ORF. The E6 oncoprotein of human papillomavirus (HPV) binds and degrades the tumour suppressor protein p53, thus contributing to tumour progression. Since BPV-4 lacks E6, it is unknown how the virus evades the tumour suppressor properties of p53 in the induction of tumours of the gastrointestinal tract. Mutations in the p53 gene have been detected both in papillomas and carcinomas, suggesting that p53 dysfunction plays a part in these neoplasias. BPV-4 can transform primary foetal bovine cells (PalFs) in cooperation with an activated ras gene, but the transformed cells are neither immortal nor tumorigenic. Co-transfection with the HPV-16 E6 (16E6) ORF confers immortality but not tumorigenicity. To investigate the role of p53 in BPV-4 cell transformation in vitro, we transfected PalFs and p53-null mouse fibroblasts with BPV-4 DNA in combinations with ras, 16E6 ORF and mutant (V143A) p53 cDNA. Transfection of PalFs with BPV-4 DNA, ras and mutant p53 led to cell immortalization, indicating that 16E6 and mutant p53 are functionally equivalent in conferring immortality. However, co-transfection of PalFs with BPV-4 DNA, ras, and both mutant p53 cDNA and 16E6 ORF resulted in cells which were fully transformed to tumorigenicity. In p53-null mouse fibroblasts, BPV-4 DNA induced transformation by itself, but the transformed cells were incapable of suspension growth. The co-transfection of BPV-4 DNA with 16E6 ORF produced many more transformed colonies and the cells were capable of growing in suspension. In this system, therefore, 16E6 confers anchorage-independence to BPV-4-transformed cells in a p53-independent fashion.
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PMID:The role of exogenous p53 and E6 oncoproteins in in vitro transformation by bovine papillomavirus type 4 (BPV-4): significance of the absence of an E6 ORF in the BPV-4 genome. 936 87

Although the mechanism remains obscure, two histological subtypes of gastric carcinoma (GC), the diffuse and intestinal types, differ drastically in epidemiological, clinical, pathological and biological characteristics. We investigated whether the genetic alterations of several oncogenes and tumour suppressor genes could be correlated with the two histological subtypes. In 60 patients with GC, the overexpression of mutant p53 and c-erbB-2 oncoproteins was studied using immunohistochemical stains. Mutations of the p15 and p16 tumour suppressor genes were assessed by polymerase chain reaction, Southern blotting, and direct DNA sequencing. Overexpression of c-erbB-2 and p53 was found in 21 (35.0%) and 27 (45.0%) patients, respectively. Overexpression of the c-erbB-2 oncoprotein was more common in the intestinal type (15/32, 46.9%) and the advanced stage (19/45, 42.2%) than in the diffuse type (6/28, 21.4%) and the early stage (2/15, 13.3%) of GC (P<0.05). Similarly, p53 overexpression was more frequently found in the intestinal type (19/32, 59.4%) and the advanced stage (24/45, 53.3%) than in the diffuse type (8/28, 28.6%) and the early stage (3/15, 20.0%) of GC (P<0.05). Homozygous deletions of p16 in exon 1 were found in six (10.0%) patients. Five of them had the intestinal-type advanced GC. Neither point mutations of p16 nor alterations of p15 were detected. The frequency of alterations of p53, c-erbB-2, and p16 was not related to sex and Helicobacter pylori infection. No correlation of genetic changes between any two genes was observed. Our preliminary results indicate alterations in the p15 gene were not important in gastric tumorigenesis, while infrequent homozygous deletions in the p16 gene play a limited role in tumour progression of intestinal-type GC. Moreover, overexpression of c-erbB-2 and p53 is frequently encountered in the intestinal-type advanced GC. Alterations of p53, c-erbB-2 and p16 genes may function independently of each other in gastric carcinogenesis. The association between genetic alterations and histological subtypes supports the notion that a distinct pathogenesis may exist in different histological subtypes.
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PMID:Overexpression of mutant p53 and c-erbB-2 proteins and mutations of the p15 and p16 genes in human gastric carcinoma: with respect to histological subtypes and stages. 957 Feb 45

Alteration of the tumour suppressor gene p53 is frequent in AIDS-related non-Hodgkin's lymphomas (AIDS-NHL), particularly in Burkitt's or Burkitt's-like lymphomas (BL/BLL). Since mechanisms of inactivation other than mutations have been advanced, the transcriptional activity of the p53 protein was studied in a functional assay in yeast in a series of AIDS-NHL lesions and compared with their morphology, immunohistochemistry (IHC) and single-strand conformation polymorphism (SSCP) analysis detection of other p53 abnormalities, Epstein-Barr virus (EBV) status, MDM-2 oncoprotein expression and c-MYC rearrangement. Polymorphic lymphoproliferations (PL), identified as precursors of NHL in HIV-patients, were also analysed in attempt to detect p53 modifications related to clonal progression. The functional assay detected p53 mutants in 40% (12/ 30) of the tumours: 50% (6/12) of BL/BLL, 40% (4/10) of diffuse large cell lymphomas (DLCL) and 25% (2/8) of PL. An oligoclonal or monoclonal population was identified in the two PL cases with mutant p53. An accumulation of the p53 protein was detected by IHC in 26% (8/30) of the tumours (five BL/BLL and three DLCL) and was associated with positive functional assay. In the 20 lesions tested by both of the screening methods for mutations, a p53 mutant pattern was detected in 55% of cases (11/20) and in 25% of cases (5/ 20) respectively with the functional assay and SSCP analysis of exons 5-8. There was no inverse correlation between the detection of EBV genome and the presence of p53 mutations and no overexpression of MDM-2 protein for the whole series. In conclusion, the functional assay was more sensitive than IHC and SSCP for the detection of p53 mutations in tumour samples. The mutations identified in AIDS-NHL lesions inactivate the p53 protein and in PL they could represent a selection of an aggressive clone.
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PMID:Functional analysis of the p53 protein in AIDS-related non-Hodgkin's lymphomas and polymorphic lymphoproliferations. 960 27

The function of p53 tumour suppressor protein is determined by various intrinsic properties of the protein. The effect of p53 DNA-binding, and protein-protein interactions are determined by the conformation of the protein. Thus, p53 fulfils its role in cell cycle control and the onset of apoptotic cell death, which is altered when the wild-type p53 (wt-p53) conformation is changed due to mutation. This review focuses on the communal interactions of wt- and mutant p53 (m-p53) with growth factors and shows that m-p53 affects different cell biological functions that determine the malignant behaviour of cells. P53, for instance, affects the response of cells to growth factors and growth factor-withdrawal. Furthermore, p53 is involved in the expression of several growth factor- and growth factor receptor genes. These data suggest that restoration of the wt-p53 phenotype in tumour cells with m-53 might not only affect cell cycle control and apoptotic mechanisms but could also reduce autocrine growth and restore sensitivity to physiological growth inhibitors.
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PMID:Mutual interactions between p53 and growth factors in cancer. 967 95

Point mutations at the tumour suppressor gene p53 are one of the most frequent genetic alterations in squamous cell carcinoma of the head and neck (SCCHN), which lead to the nuclear accumulation and overexpression of inactive p53 protein. The overexpression of mutant p53 protein can induce a specific humoral response in cancer patients. p53 protein was studied in 112 SCCHN. Biopsies and sera samples were collected before initiation of treatment. 74 patients received neoadjuvant chemotherapy (5-fluorouracil-cisplatin-folinic acid). p53 protein expression was evaluated by immunohistochemistry (IHC) on paraffin-embedded sections. The analysis of mutations was assessed by PCR-SSCP of exons 5-10 on DNA from 28 representative cases. Antibodies specific for p53 protein were analysed in sera of 74 patients by an ELISA procedure. Overexpression (> 20% positive cells) of p53 protein was frequent (56%: 63/112) and was correlated with localisation of the primary tumour and tumour stage. p53 mutations were detected in 57% (16/28) of studied cases. The prevalence of p53 antibodies in sera was high (44% 32/74) and among this population, 68% (20/29) had a positive immunophenotype and 67% (6/9) a p53 mutation in the tumour. In addition, the presence of anti-p53 antibodies was slightly associated with complete response to neoadjuvant chemotherapy. If the humoral response seems to be an indicator of the p53 protein status, the detection of anti-p53 antibodies could be a good approach in the early detection of the presence of p53 alterations in SCCHN and recurrent tumours or the appearance of second primary cancer.
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PMID:Implications of p53 alterations and anti-p53 antibody response in head and neck squamous cell carcinomas. 968 69

The tumour suppressor protein p53 is a stress-activated transcription factor whose activity is required for regulating the cellular response to stress and damage. The biochemical activity of p53 as a transcription factor can be regulated by partner proteins affecting stability, nuclear transport, signalling pathways modulating phosphorylation and interactions with components of the transcriptional machinery. The key structural determinants of p53 protein that drive sequence-specific DNA binding include the core specific DNA-binding domain and the tetramerization domain. Flanking these domains are more evolutionarily divergent carboxy- and amino-terminal regulatory motifs that further modulate tetramerization and sequence-specific transactivation. This review will mainly focus on the mechanisms whereby the tetramerization domain modulates sequence-specific DNA binding and how missense point mutations in p53 protein and the activity of molecular chaperones may lead to unfolding of mutant p53 tetramers in human tumours.
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PMID:Regulation of p53 protein function through alterations in protein-folding pathways. 1006 54

We studied the relationship between angiogenesis (using the CD34 antibody), the presence of human papilloma virus (HPV) infection, HPV E6 protein expression and the accumulation of p53 protein at various phases of tumour progression in the uterine cervix. Expression of CD34, p53 and HPV E6 protein was evaluated by immunocytochemistry. Presence of the mutant p53 was detected using a mutant specific ELISA, and the type of HPV was determined by the Polymerase Chain Reaction. A total of 230 cervical tissue samples were analyzed and included 40 cases of apparently normal cervical epithelium, 37 low grade squamous intraepithelial lesions (SILs), 43 high grade SILs, 36 well-differentiated squamous cell carcinomas (DSCC), 31 moderately differentiated (MDSCC) and 43 poorly differentiated carcinomas (PDSCC). There was an excellent correlation between the extent of angiogenesis and histological abnormality (r = 0.912, p = 0.000004). The least extent of angiogenesis was seen in normal cervical tissue and low grade SILs where the mean (low power) intra lesional vascular density (ILVD) was 12 +/- 1.13 and 25.66 +/- 5.20, respectively. In high grade squamous intraepithelial lesions (SILs), the mean ILVD value was 80.84 +/- 25.57. In well-differentiated squamous cell carcinomas (WDSCC's) the mean value was 144.22 +/- 28.67 while in moderately differentiated squamous cell carcinomas (MDSCC's) the mean value was 166.29 +/- 34.95 and in poorly differentiated tumours (PDSCC's) 192.42 +/- 27.98. The extent of angiogenesis also correlated to presence of HPV (r = 0.505, p = 0.00001). Increased CD34 expression was associated with the presence of HPV types 16 and 18. A similar correlation was also evident in HPV, 16/18 infected cases expressing the E6 protein (r = 0.612, p = 0.000001). CD34 expression also correlated well with p53 accumulation (r = 0.859, p = 0.000002). Presence of HPV infection significantly correlated with the extent of histological abnormality (r = 0.467, p = 0.00001). Expression of E6 also showed this significant correlation (r = 0.644, p = 0.00002). Accumulation of p53 was significantly more elevated in HPV 16-infected lesions (r = 0.518, p = 0.00001) and E6-expressing cells (r = 0.650, p = 0.000004). Only 12 of the 230 cases analyzed showed presence of the mutant p53 protein. Angiogenesis appears to increase with histological abnormality in the uterine cervix. Angiogenesis also appears to be influenced by high risk HPV infection, the expression of the E6 transforming protein and the p53 tumour suppressor protein.
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PMID:Increased angiogenesis in the uterine cervix associated with human papillomavirus infection. 1022 Jul 96

Mutation of the p53 tumour suppressor gene often leads to the accumulation of mutant p53 protein in tumour cells. Many cancer patients develop antibodies that recognize the overexpressed p53 protein. The presence of these antibodies is, in some tumour types, associated with poor prognosis. Gastric cancer is a highly prevalent disease associated with a high rate of mortality, there is a need for improved clinical and biological markers for disease behaviour. To investigate the clinical relevance of serum anti-p53 antibodies in patients with gastric adenocarcinoma, we have examined the sera of 501 gastric cancer patients for the presence of serum antibodies against the p53 protein. By immunoblotting analysis using a cell lysate containing overexpressed p53 protein as well as affinity-purified recombinant p53 protein as antigens, we have detected anti-p53 antibodies in 11.2% (61 of 501) of gastric cancer patients, but in none of 46 cancer-free individuals. The presence of anti-p53 antibodies was tightly associated with tumours of higher nuclear grade and lymph node metastasis, and a negative association was found between the presence of anti-p53 antibodies and survival. These results suggest that a preoperative test of serum anti-p53 antibodies in gastric cancer patients can be useful to identify subset of patients who may need gastrectomy with lymph node dissection and post-operative adjuvant therapy.
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PMID:Serum anti-p53 antibodies in gastric adenocarcinoma patients are associated with poor prognosis, lymph node metastasis and poorly differentiated nuclear grade. 1040 57


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