Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The MDM-2 gene encodes for a nuclear phosphoprotein that binds p53 and inhibits its ability to activate transcription by concealing the p53 activation domain. It has been suggested that MDM-2 overexpression might represent an alternative mechanism by which p53-mediated pathways are inactivated in human tumors. MDM-2 overexpression can be detected by immunohistochemical analysis as a result of gene amplification and/or increased mRNA expression. We studied MDM-2 gene amplification and protein overexpression in 46 and 50 cases, respectively, of laryngeal squamous cell carcinomas previously analyzed for p53 gene alterations. Not one of the cases showed MDM-2 gene amplification, whereas MDM-2 nuclear immunoreactivity was found in 17 tumors (34%). In 10 of these, coexpression of p53 protein was detectable in the absence of gene mutations in exons 5 through 9 (P = .03). Likewise, MDM-2 was also overexpressed in 18 (46%) of 39 morphologically normal mucosa samples, 15 (50%) of 30 preneoplastic lesions, and 9 (40%) of 22 cases of severe dysplasia. Finally, we found no significant correlations between MDM-2 expression (neither per se nor in association with wild-type or mutated p53), and the evaluated clinicopathologic parameters of histologic grade, lymph node status, or clinical stage. Our results suggest that MDM-2 gene amplification might not occur in laryngeal carcinomas and that MDM-2 protein overexpression might represent an alternative mechanism by which p53 is inactivated in the early stages of laryngeal cancer tumorigenesis.
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PMID:MDM-2 oncoprotein overexpression in laryngeal squamous cell carcinoma: association with wild-type p53 accumulation. 926 20

We have recently shown that human papillomavirus (HPV16) E6 oncoprotein exhibits two separate biological activities in genital keratinocytes (PHKs). E6 protein by itself is capable of inducing colonies of proliferating cells resistant to serum and calcium-induced differentiation, whereas both E6 and E7 are required for immortalization of PHK. Using epitope-tagged E6 carboxy-terminal truncation mutants, we mapped the domain between amino acid residues 132 and 141 as being essential for the induction of differentiation resistance (L. Sherman and R. Schlegel, J. Virol. 70, 3269-3279, 1996). To determine whether E6 protein's ability to alter PHK response to serum and calcium was associated with its ability to inactivate p53, we evaluated each of the above E6 mutants and three E6 natural variants in these respective assays. Our results demonstrate that the E6 region spanning residues 132-141 is required for p53 degradation and for abrogation of p53 transactivation, suggesting a possible correlation between E6 biological activity in altering differentiation and loss of p53 function. To evaluate whether selective inactivation of p53 is sufficient for altering the response of PHK to serum and calcium we investigated the capacity of plasmids encoding a dominant mutant human p53 and human MDM-2 to functionally substitute for E6 in colony formation in PHK. Plasmids were verified for their ability to inactivate wild-type p53 by testing their capacity to abrogate the p53 transactivation function. The results obtained showed that vectors encoding human MDM-2 and mutant p53, while active in inhibition of p53-dependent transactivation and capable of expressing stable proteins in PHK, failed to induce colonies of proliferating cells resistant to serum and calcium differentiation. These data argue that p53 inactivation may not be the sole E6 function required for altering the response of PHK to serum- and calcium-triggered differentiation.
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PMID:Inhibition of serum- and calcium-induced differentiation of human keratinocytes by HPV16 E6 oncoprotein: role of p53 inactivation. 935 41

Detection of various epitopes of the p53 and MDM-2 proteins, using new antibodies was performed on formalin-fixed and paraffin-embedded tissue samples from breast cancer and compared with results obtained using well-characterized antibodies. The results show that the distribution of positive nuclei and intensity of staining varies significantly depending on the antibody used, as well as on the microwaving procedure. Antibodies DO-14, DO-13 and SMP-14 have very good characteristics and are available for immunohistochemical analysis of p53 and MDM-2. Our results indicate, that immunohistochemical expression of p53 and MDM-2 is a not stable and unitary phenomenon and from this point of view a single antibody is not sufficient for its determination. Since, characteristics of p53 and MDM-2 molecules can vary from one sample to the next, panel antibodies capable of determining a wide range of wide type and mutant conformations must be used.
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PMID:Immunoreactivity of new antibodies anti-p53 and anti-MDM-2 in paraffin embedded tissue samples. 943 95

The immunohistochemically detected expression of p53, BCL-2, MDM-2 and PCNA proteins in samples of tumor tissues of 42 patients with astrocytomas or glioblastoma multiforme was statistically compared to degree of malignancy and overall survival. We found relation between p53 protein expression and survival in the high grade astrocytomas group (more cases of p53 immunonegative tumors with longer survival), and significantly higher BCL-2 protein expression as well as significantly higher MDM-2 protein expression in the group of low grade astrocytomas. PCNA protein expression showed any relation to tumor grade or survival. Despite the rather small number of samples these results support the hypothesis that MDM-2 protein may be a potent regulator of functional p53, expressed in low grade astrocytoma only.
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PMID:Prognostic factors in astrocytomas: relationship of p53, MDM-2, BCL-2 and PCNA immunohistochemical expression to tumor grade and overall patient survival. 947 89

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 P53 gene is frequently mutated in late stage ovarian cancer and has been proposed as a determinant of radiation and chemosensitivity. We have therefore determined the p53 functional status, P53 sequence, radiation sensitivity and cytotoxicity of cisplatin and the novel platinum analogue, AMD473, in a panel of 6 human ovarian cancer cell lines. Constitutive p53 protein levels were low in A2780, CH1, LK1, LK2 and PA1 but were markedly induced following irradiation. In OV1P, constitutive p53 protein was readily detectable and levels were induced slightly following irradiation. p21WAF1/CIP1 and MDM-2 mRNA were constitutively expressed in all the cell lines and expression was induced markedly following irradiation. There was marked radiation induced G1/S arrest in A2780 but only partial arrests in CH1, LK1, LK2, PA1 and OV1P lines. No mutations were found in A2780, CH1, LK1, LK2 and PA1 cells by single-strand conformational polymorphism (SSCP) analysis but a heterozygous point mutation was found in exon 5 of OV1P. All the cell lines were radiation sensitive and also relatively sensitive to cisplatin; however, OV1P was the most resistant being consistent with its heterozygous P53 status. AMD473 was less potent than cisplatin but a similar pattern of drug sensitivity was observed with the exception of LK2, which was resistant. CH1, LK1, LK2 and PA1 all expressed BCL-2 protein but there was no expression in A2780 and OV1P. Our results suggest an overall association between wild type P53 and radiation and platinum drug sensitivity in these ovarian cancer cell lines.
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PMID:Characterisation of the p53 status, BCL-2 expression and radiation and platinum drug sensitivity of a panel of human ovarian cancer cell lines. 971 63

To evaluate the predictive role of the oncogenes p53, MDM-2 and cyclin D1, and the proliferative marker Ki67, in the progression from low-grade dysplasia to carcinoma of the larynx. We studied immunohistochemically a series of 32 low-grade pre-neoplastic laryngeal lesions, 10 of which progressed to invasive carcinoma. Immunoreactivity in more than 10 per cent of the dysplastic cells was detected in five cases immunostained with anti-p53 (approximately 15 per cent), in two with anti-MDM-2 (approximately six per cent), and 11 with anti-Ki67 antibodies (approximately 34 per cent), whereas none of the cases showed cyclin D1 overexpression. No significant association was found between p53 and MDM-2 immunoreactivity and the evolution to carcinoma; on the contrary, Ki67 expression was detectable in all but one of the 10 cases developing an infiltrative tumour (90 per cent), and in two of the 22 cases that did not progress (approximately nine per cent) (p = 0.01). These findings indicate that immunohistochemical assessment of the proliferative index in bioptic samples of dysplastic laryngeal mucosa may be useful in selecting patients who should undergo a more specific follow-up evaluation.
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PMID:The predictive value of p53, MDM-2, cyclin D1 and Ki67 in the progression from low-grade dysplasia towards carcinoma of the larynx. 974 74

Wild-type p53 plays a crucial role in the control of apoptosis following ionizing radiation (IR); conversely, mutant p53 is associated with IR resistance. Although wild-type p53 is expressed in virtually all neuroblastoma tumors, treatment failures secondary to inadequate local control with radiotherapy are a problem in patients with advanced stage disease. This apparent paradox is the focus of our interest. The Shep-1 neuroblastoma cell line is highly resistant to IR. This cell line contains a wild-type p53 gene and is an ideal model for studying the mechanism of IR resistance in this disease. Following high-dose IR, cell fractionation demonstrated that p53 is induced and targeted to the nucleus. The induced p53 is functional as p53-responsive genes (Waf-1 and MDM-2) are appropriately induced following IR. Intriguingly, overexpression of p53 could reverse the inherent IR resistance of Shep-1 cells. Multiple cell lines expressing variable levels of exogenous temperature-sensitive p53 were generated. Pulse induction of p53 alone did not affect Shep-1 cell viability, while induction of p53, followed by IR, resulted in cell death and DNA fragmentation proportional to the dose of IR and the level of p53 expression. These findings demonstrate that p53 overexpression renders Shep-1 cells IR-sensitive and suggest that large quantities of exogenous p53 can overcome the factors inhibiting p53-mediated, IR-induced apoptosis.
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PMID:Role of p53 in the regulation of irradiation-induced apoptosis in neuroblastoma cells. 978 7

The endothelium is one of the largest cellular compartments of the human body and has a high proliferative potential. However, angiosarcomas are among the rarest malignancies. Despite this interesting contradiction, data on growth and angiogenesis control mechanisms of angiosarcomas are scarce. In this study of 19 angiosarcomas and 10 benign vascular control lesions we investigated the sequence and expression of the p53 tumor suppressor gene and the expression of the mdm-2 proto-oncogene, which is a negative regulator of p53 activity and of the vascular endothelial growth factor (VEGF), whose expression, among other factors, is regulated by the p53/MDM-2 pathway. Ten sarcomas (53%) exhibited clear nuclear p53 protein accumulation. Two of these cases revealed mutations in the sequence-specific DNA binding domain of the p53 gene. Thirteen angiosarcomas (68%) showed an increased amount of MDM-2 protein. Elevated expression of p53 and MDM-2 protein correlated with increased VEGF expression, which was found in nearly 80% of the angiosarcoma cases. Negative or clearly lower immunostaining was obtained in cases from the benign control collective. Only one case of a juvenile hemangioma reached the cutoff value of p53 positivity coincidentally with high VEGF expression. Our data suggest that the p53/ MDM-2 pathway is impaired in about two-thirds (14/ 19) of the angiosarcomas. This may be a key event in the pathogenesis of human angiosarcomas. The increased VEGF expression observed supports this hypothesis.
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PMID:MDM-2 oncoprotein overexpression, p53 gene mutation, and VEGF up-regulation in angiosarcomas. 981 33

Less than 30% of malignant gliomas respond to adjuvant chemotherapy. Here, we asked whether alterations in the p53 and RB pathways and the expression of six BCL-2 family proteins predicted acute cytotoxicity and clonogenic cell death induced by BCNU, vincristine, cytarabine, teniposide, doxorubicin, camptothecin or beta-lapachone in 12 human malignant glioma cell lines. Neither wild-type p53 status, nor p53 protein accumulation, nor p21 or MDM-2 levels, nor differential expression of BCL-2 family proteins predicted drug sensitivity, except for an association of BAX with higher beta-lapachone sensitivity in acute cytotoxicity assays. p16 protein expression was associated with high doubling time and chemoresistance. We conclude that some important molecular changes, which are involved in the development of gliomas and attributed a role in regulating vulnerability to apoptosis, may not determine the response to chemotherapy in these tumors.
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PMID:Predicting chemoresistance in human malignant glioma cells: the role of molecular genetic analyses. 984 75


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