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)

Although most pituitary tumors are well differentiated, histologically benign neoplasms, their clinical behavior is known to vary greatly. These lesions are relentlessly aggressive in some instances yet biologically indolent in others, but these prognostically relevant differences in behavior are not reflected in their histopathological appearance. As a means of identifying intrinsically aggressive pituitary tumors, we evaluated 70 pituitary adenomas and 7 primary pituitary carcinomas for their expression of the p53 gene product, a nuclear phosphoprotein whose immunohistochemical accumulation has served as an unfavorable prognostic factor for a wide range of human neoplasms. All tumors were fully classified by immunohistochemistry and electron microscopy; adenomas were further stratified on the basis of their invasion status, the latter being defined as gross operatively or radiologically apparent infiltration of dura or bone. Conclusive nuclear immunopositivity for p53 was identified in a total of 12 tumors, all being either invasive adenomas or primary pituitary carcinomas. A clear and highly significant association was evident between p53 expression and tumor behavior, as the proportion of p53-positive cases among noninvasive adenomas, invasive adenomas, and pituitary carcinomas was 0, 15.2, and 100%, respectively (chi 2 = 44.72; degrees of freedom, 2; P << 0.001). A comparison of previously reported growth fraction data with p53 expression indicated that the mean Ki-67-derived growth fraction of p53-positive tumors was significantly higher than that of p53-negative tumors (10.41 +/- 2.20 versus 2.51 +/- 0.28%) (+/- standard error of the mean, two-sample t test for independent samples, P = 0.004). There was no apparent relationship between the functional status of the tumor and p53 expression; positivity was observed among somatotroph, lactotroph, corticotroph, and clinically nonfunctioning pituitary tumors. These data indicate that p53 expression, when conclusively present in pituitary tumors, may be of some diagnostic usefulness as a marker of biologically aggressive behavior.
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PMID:p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions. 869 97

The mdm2 oncogene encodes a 90-kilodalton nuclear phosphoprotein that binds and inactivates the p53 tumor suppressor protein. Here we report the observation of five alternatively spliced mdm2 gene transcripts in a range of human cancers and their absence in normal tissues. Transfection of NIH 3T3 cells with each of these forms gave foci of morphologically transformed cells. A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding, consistent with partial deletion of sequences encoding the p53 binding domain, but retain carboxyterminal zinc-finger domains. These observations suggest a reassessment of the transforming mechanisms of mdm2 and its relation to p53.
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PMID:Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. 870 62

The mechanism of negative growth regulation by the nuclear phosphoprotein p53 in breast cancer cells may rely on its role as a transcriptional activator of cell cycle-related genes. We have tested this hypothesis using retrovirally transduced wild-type (wt) p53 in breast cancer cell lines containing homozygously endogenous mutant (mt) p53. Restoring the expression of wt p53, the percentage of cells in S phase was reduced, G1/S transition was slowed, and progression through S was restrained. The fraction of cells with a flattened "Cdk-minus" phenotype increased 5- to 10-fold. High constitutive mRNA expression of the cyclin-Cdk inhibitor WAF1 in MDAMB231 cells was not induced upon restored wt p53 expression suggesting a p53-independent pathway in the regulation of WAF1 mRNA expression. Wt p53 acted trans-dominantly in the presence of accumulating mt p53 and installed a modulation of G1/S transition and S phase progression independent of WAF1 expression.
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PMID:Retrovirally mediated wild-type p53 restores S-phase modulation without inducing WAF1 mRNA in breast carcinoma cells containing mutant p53. 874 22

The presence of the nuclear phosphoprotein p53 was investigated in a series of 120 consecutive gastric carcinomas. This immunohistochemical study on formalin-fixed, paraffin-embedded material found p53 expression in 43 per cent (n = 51) of carcinomas using a monoclonal antibody (DO-1), whereas no immunoreactivity for p53 was present in tumour-associated non-neoplastic gastric mucosa or tumour stroma. There was no statistically significant correlation with known prognostic parameters such as extent of tumour growth (pT state), nodal involvement (pN state), or tumour grade. The same applied for association with patient age and sex or pathological parameters such as tumour size, localization, or growth pattern according to histological classification. Kaplan-Meier analysis revealed marginal statistically significant differences in survival times between patients with p53-positive tumours with more than 35 per cent of p53-positive tumour cells and those with less than 35 per cent of p53-positive tumour cells or p53-negative tumours (P = 0.04). However, by multivariate analysis, p53 immunoreactivity did not turn out as an independent prognostic parameter. p53 expression can easily be detected in a variety of human malignancies including gastric cancer by immunohistochemical methods, but its prognostic significance and possible role as an independent marker of poor prognosis still have to be confirmed by further studies.
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PMID:Prognostic influence of p53 expression in gastric cancer. 915 24

The p53 gene, which is located on human chromosome 17, encodes for a nuclear phosphoprotein and is thought to regulate cell growth and proliferation. Although the immunoreactivity for p53 oncoprotein in transitional cell carcinoma (TCC) of the urinary bladder has been shown to correlate with clinicopathologic findings and prognoses, there have been no such reports on TCC of the upper urinary tract (TCC-UUT). The present study investigated the prognostic value of p53 oncoprotein in TCC-UUT. Formalin-fixed, paraffin-embedded tumor tissues from 149 TCC-UUT patients were analyzed using immunohistochemical staining. Immunohistochemically, p53 oncoprotein was recognized as positive in 26.8% of the samples. The immunoreactivity for p53 oncoprotein was significantly (P < .05) correlated with both stage, grade, and pattern of growth. The 5-year disease-free and overall survival rates were 58.4% and 69.7%, respectively. A univariate analysis of survival showed that stage, grade, pattern of growth, and the immunoreactivity for p53 oncoprotein have a significant effect on disease-free and overall survival rates. In the final models of multivariate analysis, only stage for disease-free survival, and stage and the immunoreactivity for p53 oncoprotein for overall survival were found to be progressive or prognostic factors. Detection of immunoreactivity for p53 oncoprotein appears to be of real value in deciding the prognosis of TCC-UUT.
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PMID:Immunohistochemical evaluation of p53 oncoprotein in transitional cell carcinoma of the upper urinary tract. 895 8

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

The gene coding p53 is commonly affected by deletions, rearrangements, or point mutations in a variety of human cancers. p53 is a nuclear phosphoprotein. Mutations are frequently found at highly conserved residues of the p53 protein. The mutant p53 proteins examined so far each have a much longer half-life than that of the wild-type p53 protein which is rapidly degraded under normal conditions. Alterations of p53 protein conformation result in the accumulation of such protein usually in transformed cells or cancer cells. The p53 protein is a sequence-specific DNA-binding protein that is active as a transcription factor. The genes coding p21, GADD45, mdm2, cyclin G etc. contain such a p53 responsive element. Upon exposure of cells to ionizing radiation, ultraviolet light, or DNA-damaging agents, high levels of p53 accumulate, resulting in subsequent stimulation of a series of p53-responsive genes and cell cycle arrest or apoptosis. The function of p53 is also linked to DNA synthesis via interaction with p21 and PCNA. The pathways involving p53 seem to be extremely complicated but may play an important role in the core function of cell growth.
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PMID:[p53]. 930 29

The tumour suppressor gene p53 is a nuclear phosphoprotein whose correct functioning is crucial for an appropriate cellular response to DNA damage. It has been suggested that p53 may act as a 'guardian of the genome' since when DNA damage is mild, p53 functions to halt cell cycle progression allowing DNA repair to occur before progression through the cell cycle. This prevents 'fixing' of lesions into the genome during replication. However when DNA damage is severe and irreversible, p53 induces the cell to undergo apoptosis. Recent studies have demonstrated DNA fragmentation and increased expression of p53 within neurons after injury. It appears that p53 expression may precede DNA fragmentation suggesting that rather than being induced in neurons in response to DNA damage, p53 expression may actually initiate neuronal apoptosis leading to DNA fragmentation. Recent reports documenting the resistance of neurons derived from p53-null mice (p53-/-) to excitotoxicity and DNA damaging agents both in vitro and in vivo and showing that p53 overexpression induces neuronal apoptosis in vitro support a role for the tumour suppressor gene p53 in regulating neuronal apoptosis. Here we review the recent evidence and discuss likely mechanisms involved in p53-mediated neuronal apoptosis.
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PMID:A role for the tumour suppressor gene p53 in regulating neuronal apoptosis. 935 39

The tumor suppressor protein p53 acts as a transcriptional activator that can mediate cellular responses to DNA damage by inducing apoptosis and cell cycle arrest. p53 is a nuclear phosphoprotein, and phosphorylation has been proposed to be a means by which the activity of p53 is regulated. The cyclin-dependent kinase (CDK)-activating kinase (CAK) was originally identified as a cellular kinase required for the activation of a CDK-cyclin complex, and CAK is comprised of three subunits: CDK7, cyclin H, and p36MAT1. CAK is part of the transcription factor IIH multiprotein complex, which is required for RNA polymerase II transcription and nucleotide excision repair. Because of the similarities between p53 and CAK in their involvement in the cell cycle, transcription, and repair, we investigated whether p53 could act as a substrate for phosphorylation by CAK. While CDK7-cyclin H is sufficient for phosphorylation of CDK2, we show that p36MAT1 is required for efficient phosphorylation of p53 by CDK7-cyclin H, suggesting that p36MAT1 can act as a substrate specificity-determining factor for CDK7-cyclin H. We have mapped a major site of phosphorylation by CAK to Ser-33 of p53 and have demonstrated as well that p53 is phosphorylated at this site in vivo. Both wild-type and tumor-derived mutant p53 proteins are efficiently phosphorylated by CAK. Furthermore, we show that p36 and p53 can interact both in vitro and in vivo. These studies reveal a potential mechanism for coupling the regulation of p53 with DNA repair and the basal transcriptional machinery.
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PMID:p53 is phosphorylated by CDK7-cyclin H in a p36MAT1-dependent manner. 937 54

The mdm2 oncogene encodes a 90-kDa nuclear phosphoprotein that binds and inhibits the function of the p53 tumor suppressor protein. It was recently reported that the expression of alternatively spliced variants of mdm2 correlated with malignancy in ovarian tumors and bladder carcinomas. We analyzed the presence of alternatively spliced mdm2 variants and studied their correlation to p53 status in a total of 66 human astrocytic tumors, including 32 glioblastomas multiforme, 17 anaplastic astrocytomas, 12 astrocytomas, and 5 pilocytic astrocytomas, using a specific nested reverse transcription-PCR technique. The full-length mdm2 transcript was demonstrated in all of the cases. Multiple-sized PCR products were found in 29 cases. Two of 5 pilocytic astrocytomas (40%), none of 12 astrocytomas, and 5 of 17 anaplastic astrocytomas (29%) showed alternative splice variants. In contrast, 22 of 32 glioblastomas (69%) showed the presence of splice variants, demonstrating a significantly higher frequency than in lower-grade astrocytomas (P < 0.0003). A majority of the splice variants were 707 base-type (mdm2-b), which was confirmed by sequence analysis. There was no apparent correlation of the presence of mdm2 splice variants with p53 gene status. These results suggest a new role for mdm2, independent of p53 gene status, as an oncogene in the development of malignant astrocytic tumors.
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PMID:Short alternative splice transcripts of the mdm2 oncogene correlate to malignancy in human astrocytic neoplasms. 948 8


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