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)

Despite good evidence for p53 dysfunction in human hepatocellular carcinomas, little is known of the significance of p53 to normal hepatocytes and whether p53 dysfunction is relevant to early hepatocarcinogenesis. We have therefore examined the consequences of targeted p53 deficiency in hepatocytes for regulation of apoptosis, proliferation, and ploidy. p53 deficiency was silent in normal liver and did not affect progression from diploidy to polyploidy in the aging liver. However, in primary culture the absence of p53 resulted in increased hepatocyte proliferation indices and decreased sensitivity to proliferation inhibition by TGFbeta. Moreover, p53-deficient cells continued to survive and proliferate under conditions of minimal trophic support that led to growth arrest and apoptosis of wild-type cells. In vivo, p53-deficient mice had enhanced proliferative responses to both xenobiotic hepatomitogen and CCl4-induced liver necrosis, although lack of persistent proliferation showed that other control mechanisms are important. There was no simple relationship between p53 and apoptosis after DNA damage because UV irradiation led to p53-independent apoptosis, even though p53 was stabilized. However, p53 did couple DNA damage to growth arrest, and abnormal mitoses after gamma-irradiation of regenerating p53 null livers demonstrated circumstances where loss of G1 and G2 checkpoints may generate abnormal ploidy. Thus p53 becomes important when hepatocytes are released from G0 and stressed, sensitizing them to mitogen and cytokine regulators of cell cycle progression and apoptosis. Hence p53 deficiency is likely to be significant in an environment of persistent regenerative stimuli and unfavorable trophic support or in the presence of other enabling genetic lesions. This model is relevant to human hepatocarcinogenesis, which almost always occurs against a background of chronic hepatocellular destruction in hepatitis and cirrhosis. In that context, by reducing the need for cytokine support and disabling DNA damage-induced growth arrest, p53 deficiency should facilitate the expansion of preneoplastic clones in chronic liver disease.
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PMID:p53 Deficiency in liver reduces local control of survival and proliferation, but does not affect apoptosis after DNA damage. 921 83

The incidence of p53 gene aberrations is reported to be about 20-50% in hepatocellular carcinomas (HCCs). In most cases, HCC is clinically preceded by liver cirrhosis, but the genetic changes in cirrhosis are not known well. Therefore, we studied the loss of heterozygosity (LOH) of the p53 gene in cirrhotic and neoplastic foci in the livers of patients with HCC. To assess the relationship between the LOH status of the p53 gene in the liver cirrhosis stage and that in HCC, we analyzed the samples microdissected from paraffin-embedded tissues using the polymerase-chain-reaction-based assay. We studied 18 patients with HCC. Fourteen of the 18 cases showed constitutional heterozygosity for the microsatellite markers. In 8 (57%) of the 14 informative cases, LOH was detected in primary HCCs. Among these 8 doubly informative (informative and LOH positive in primary HCC) cases, 5 cases (63%) showed LOH in liver cirrhosis lesions. The pattern of p53 allelic loss in the cirrhotic foci was identical with that in the corresponding tumor. The remaining 6 cases without LOH of the p53 gene in HCC showed on p53 loss in any cirrhotic foci. LOH of the p53 gene may occur before the development of HCC.
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PMID:Loss of the tumor suppressor p53 gene at the liver cirrhosis stage in Japanese patients with hepatocellular carcinoma. 921 55

Angiogenesis, the formation of new microvessels from parent microvessels, involves remodeling the basement membrane and interstitial extracellular matrix (ECM) using degrading proteases produced by the endothelial cells (ECs) and other adjacent cells, and the synthesis of ECM molecules by these cells. Degraded ECM releases previously bound heparin-binding cytokines (and growth factors) which are able to act as ligands to high-affinity receptors on various target cells, including ECs. The EC carries receptors for a number of cytokines which are produced by neighboring cells or released from the ECM and which can either induce or suppress the angiogenic phenotype of the EC. ECs are able to synthesize and secrete cytokines with auto- and paracrine effects. Angiogenesis, which virtually never occurs physiologically in adult tissues (except in the ovary, the endometrium and the placenta), is essential in wound healing and inflammation. Angiogenesis is, in fact, strictly controlled by a redundancy of pro- and anti-angiogenic paracrine peptide molecules, some of which have recently been described. The expression and synthesis of two distinct anti-angiogenic factors is, for example, controlled by the p53 tumor suppressor gene. In certain hypoxic conditions, chronic inflammatory diseases and syndromes, angiogenesis is of pathogenic and prognostic significance. Angiogenesis is, moreover, essential for the growth and metastatic spread of solid tumors. This indicates the potential for developing new therapeutic strategies not only for tumors but also in diseases such as rheumatoid arthritis, psoriasis, liver cirrhosis and diabetic retinopathy. Moreover, the therapeutic induction of angiogenesis in ischemic tissues using recombinant cytokines is also promising for clinical application. In fact, the first successful human gene therapy for stimulating angiogenesis has recently been reported.
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PMID:Angiogenesis: new aspects relating to its initiation and control. 923 59

Mutations in the p53 gene with generation of circulating autoantibodies to p53 protein (anti-p53) have been recently detected in a significant proportion of patients with different malignant diseases. Using ELISA methods we assessed alpha-fetoprotein (AFP) and anti-p53 as serological screening parameters for hepatocellular carcinoma (HCC) in 147 consecutive patients with hepatitis C virus-related chronic hepatitis. Liver cirrhosis was histologically diagnosed in 58 patients (39,5%) and a HCC confirmed in 7 patients (4.8%). Serum AFP levels were raised above 20 ng/ml in 26/147 patients (17.7%) and above 100 ng/ml in 5/147 patients (3.4%). In 6/7 patients with HCC serum AFP was raised above 20 ng/ml, but only in 3/7 cases above 100 ng/ml. Autoantibodies to p53 protein were detected in 3/7 patients with HCC, but in 0/140 patients without HCC (sensitivity 42.9%, specificity 100%). In conclusion, the presence of anti-p53 was specific for malignancy and independent of AFP status. Overall, the sensitivity of serological screening for HCC in patients with hepatitis C virus-related chronic hepatitis was improved by combining AFP measurements (level > 100 ng/ml) with the detection of anti-p53.
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PMID:Anti-p53 autoantibodies in hepatitis C virus-infected patients. 932 6

Forty-two patients with hepatocellular carcinoma (HCC) were resected and their tumours were analysed for p53 mutations by GC-clamped denaturing gradient gel electrophoresis (DGGE), single-strand conformation polymorphism (SSCP) and gene sequencing. All the exons have been analysed in this study. Eight of 12 HCCs with cirrhosis due to viral hepatitis and the two patients with sarcomatoid changes displayed p53 mutations. In contrast, no mutation was observed in the fibrolamellar variant (n = 9), non-cirrhotics (n = 13) and alcoholic cirrhosis (n = 6). The mutations observed were in exons 5-8. Two mutations were observed in codons 136 and 213 as well as a T insertion between residues 156 and 157 (exon 5) and these are reported for the first time in HCC. Likewise, the silent mutation polymorphism in codon 213 was noticed in 3 of the 42 patients. Survival analysis of these patients after surgery showed the mean and median survival in patients with wild-type p53 to be 60 and 43 months respectively. In the group with p53 mutations, the mean and median survival was 15 and 12 months. The difference was statistically significant (P= 0.003).
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PMID:p53 mutation is a poor prognostic indicator for survival in patients with hepatocellular carcinoma undergoing surgical tumour ablation. 951 57

Mutation of the p53 gene has been reported in hepatocellular carcinoma (HCC) occurring worldwide. The most frequent p53 mutation has been found in HCCs in regions with high hepatitis B virus (HBV) infection and intake of aflatoxin B1 (AFB1). The aim of our study was to examine p53 protein expression in HCCs from a high incidence area of Guangxi, Southern China, where HBV infection and dietary intake of AFB1 are high. Immunohistochemical staining of p53 protein was carried out using a polyclonal rabbit antibody (CM-1). Serial sections were also stained for hepatitis B surface antigen and core antigen. p53 Protein expression was detected in 13 (43.3%) of the 30 HCCs. Expression of p53 was found in 25.0% (1/4) of the < or = 5.0 cm diameter HCCs, in 36.8% (7/19) of the 5.1-10.0 cm diameter HCCs and in 71.4% (5/7) of the >10.0 cm diameter HCCs. Expression of p53 was observed more in moderately and poorly differentiated than in the well differentiated HCCs and more frequently seen in HCCs from younger patients. These data indicate that there is a close association between p53 protein expression and tumor size, histological grade and age of patients. Twenty-seven out of 30 cases (90.0%) were positive for HBV. No significant association between p53 expression and sex. HBV infection, cirrhosis or alpha-fetoprotein has been found.
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PMID:p53 protein expression in patients with hepatocellular carcinoma from the high incidence area of Guangxi, Southern China. 957 Mar 60

The inducible nitric oxide synthase (iNOS) gene is expressed by hepatocytes in a number of physiologic and pathophysiologic conditions affecting the liver including septic and hemorrhagic shock. The molecular regulation of iNOS expression is complex and occurs at multiple levels in the gene expression pathway. The cytokines TNF-alpha, IL-1beta, and INF-gamma synergistically activate iNOS expression in the liver, and the human iNOS gene was first cloned from cytokine-stimulated hepatocytes. iNOS expression requires the transcription factor NF-kappaB and is down-regulated by steroids, TGF-beta, the heat shock response, p53, and nitric oxide (NO) itself. In vivo, hepatic iNOS induction is differentially regulated from the typical acute-phase reactants and is not expressed as a mandatory component of the acute phase response. Thus, numerous mechanisms have evolved to regulate iNOS expression during hepatocellular injury. Studies of the effects of NO in the liver demonstrate that induced NO synthesis plays an important role in hepatocyte function and protects the liver during sepsis and ischemia reperfusion. Its cytoprotective role is best exemplified in a rodent model of endotoxemia. Here the addition of the nonspecific NOS inhibitors significantly increased hepatic damage. NO exerts a protective effect through its ability to prevent intravascular thrombosis by inhibiting platelet adhesion and neutralizing toxic oxygen radicals. NO also exerts a protective effects both in vivo and in vitro by blocking TNF-alpha-induced apoptosis and hepatotoxicity, in part by a thiol-dependent inhibition of caspase-3-like protease activity. These studies demonstrate the cytoprotective effects of NO in the liver and suggest hepatic iNOS expression functions as an adaptive response to minimize inflammatory injury. In addition, NO has anti-tumor effects as well as known mutagenic effects, is involved in the systemic vasodilatation of cirrhosis, and has potent antimicrobial properties.
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PMID:Inducible nitric oxide synthase in the liver: regulation and function. 972 29

In hepatocellular carcinoma (HCC) of patients from the Western hemisphere, mutations in the p53 tumour suppressor gene are present in up to 37% of cases. Conformational change and cellular accumulation can initiate an immune response with generation of circulating autoantibodies to p53 protein. In the present study, we investigated 711 consecutive patients with chronic liver disease to evaluate the sensitivity and specificity of autoantibodies to p53 protein as a serological marker for HCC. Detection of p53 autoantibodies was performed using an enzyme-linked immunosorbent assay with immobilised recombinant p53 protein. Liver cirrhosis was present in 259 patients (36.4%) and a HCC was diagnosed in 75 patients (10.6%). Autoantibodies to p53 protein were detectable in 15 of 377 patients with chronic liver disease (4.0%) and in 10 of 259 patients presenting with liver cirrhosis (3.9%). All 25 p53 autoantibody-positive/HCC-negative patients were carefully investigated and no underlying malignancy was clinically detected, suggesting that elevated p53 antibody levels may not exclusively be detectable in patients with malignant disease. In patients with clinically manifest HCC, p53 autoantibodies were detected in 17 of 75 cases, thus resulting in a sensitivity of 22.7% and a specificity of 96.1%. In contrast, assessment of serum alpha-fetoprotein (AFP) resulted in a sensitivity and specificity of 69.3 and 91.8% (AFP > 20 ng/ml) and 53.3 and 99.1% (AFP > 100 ng/ml) for the detection of HCC, respectively. The data of the present study reveal that the presence of p53 autoantibodies in patients with chronic liver disease is not completely specific for HCC. Moreover, we obtained no direct evidence that p53 autoantibody formation precedes the clinical diagnosis of HCC. However, serological screening for HCC might be improved by combining AFP and p53 autoantibody assays.
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PMID:Clinical evaluation of autoantibodies to p53 protein in patients with chronic liver disease and hepatocellular carcinoma. 984 79

The X gene product of the hepatitis B virus (HBV) genome functions as a transactivating element and it is considered as an essential factor for establishing chronic infection as well as for hepatocarcinogenesis. Its interaction with the product of the p53 tumor suppressor gene could be responsible for the intensification of cellular proliferation. We assessed the presence of X protein in biopsy samples of chronic hepatitis (CH), cirrhosis (CiH) and hepatocellular carcinoma (HCC) tissues comparing to the presence of other viral markers (HBcAg, HBsAg) using immunohistochemical methods. We sought the expression of p53 gene in the same tissue samples and analysed the possibility of its accumulation in detectable quantity at different stages of the disease. Our results indicate a higher positivity for the X protein than for HBs and HBc antigens (p < 0.05). HBx expression in liver cells during chronic HBV infection may be a prognostic marker for the development of HCC. The p53 protein was not detectable in the majority of non-malignant tissues; thus its inactivation seems to be more likely a late event in carcinogenesis.
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PMID:[The determination of the viral markers of the hepatitis B virus and protein p53 in liver biopsy samples]. 993 5

To examine the significance of aberrant DNA methylation in hepatocarcinogenesis, the DNA methylation status at the D17S5 locus and mRNA expression of a candidate tumor suppressor gene, HIC-1 (hypermethylated-in-cancer), which was identified at the D17S5 locus, in primary hepatocellular carcinomas (HCCs) and their corresponding noncancerous liver tissues were assessed. DNA hypermethylation at the D17S5 locus was detected in 44% of the noncancerous liver tissues showing chronic hepatitis or cirrhosis, which are widely considered to be precancerous conditions, but was not observed in noncancerous liver tissues showing no remarkable histological findings. The incidence of DNA hypermethylation at this locus was significantly higher in HCCs (90%) than noncancerous liver tissues (P <.001). Loss of heterozygosity at the D17S5 locus, which was preceded by DNA hypermethylation at the same locus, was detected in 54% of HCCs. The HIC-1 mRNA expression level of noncancerous liver tissues showing chronic hepatitis or cirrhosis was significantly lower than that of noncancerous liver tissues showing no remarkable histological findings (P <.01), and that of HCCs was even lower than that of noncancerous liver tissues (P <.05). Poorly differentiated HCCs showed lower expression levels than well- to moderately differentiated HCCs. Mutation of the p53 gene may be involved in HIC-1 inactivation. Moreover, wild-type p53 did not overcome DNA hypermethylation at the D17S5 locus to activate HIC-1 in HCCs. These data suggest that aberrant DNA methylation at this locus and reduced HIC-1 mRNA expression participate in hepatocarcinogenesis during both early developmental stages and malignant progression of HCCs.
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PMID:DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis. 1005 71


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