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)

Loss of heterozygosity (LOH) on chromosome 13q is one of the most common genetic alterations in hepatocellular carcinoma (HCC) and might be involved in liver cancer development through inactivation of tumour suppressor genes. In order to narrow down the region of 13q loss, we examined the pattern of loss of heterozygosity (LOH) in tumours from 88 HCC patients, using 18 microsatellite markers on 13q. Thirty-eight of the 88 tumours (43%) showed LOH for at least one marker. Of these, two tumours (5%) showed 13q whole arm allelic loss, while the remaining 36 tumours (95%) had partial allelic loss. The LOH pattern defined by the 36 tumours suggested the existence of at least three different smallest common deleted regions which might be involved in the carcinogenesis of HCC. The first, the most centromeric in the 13q12.3 is, close to the BRCA2 gene, defined by D13S171; the second, the most telomeric region in the 13q31-32 band, is defined by D13S154 and D13S157; the third, the intermediate region at 13q14.3, which is near the RB gene, is defined by loci D13S268. The rate of LOH at 13q31-32 was significantly higher in Hepatitis B-surface antigen (HBsAg)-positive patients than HBsAg-negative HCC patients, pointing to a candidate gene related to the development of HBsAg-positive HCCs.
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PMID:Loss of heterozygosity at chromosome 13q in hepatocellular carcinoma: identification of three independent regions. 1067 21

The p73 gene has been mapped to 1p36.33, a region which is frequently deleted in a wide variety of neoplasms including tumours of neuroectodermal origin. The p73 protein shows structural and functional homology to p53. For these reasons, p73 was considered as a positional and functional candidate tumour suppressor gene. Thus far, mutation analysis has provided no evidence for involvement of p73 in oligodendrogliomas, lung carcinoma, oesophageal carcinoma, prostatic carcinoma and hepatocellular carcinoma. In neuroblastoma, two mutations have been observed in a series of 140 tumours. In view of the occurrence of 1p deletions in Merkel cell carcinoma (MCC) and the location of p73 we decided to search for mutations in the p73 gene in five MCC cell lines and ten MCC tumours to test potential tumour suppressor function for this gene in MCC. In view of the possible complementary functions of p73 and TP53 we also examined the status of the TP53 gene. Sequence analysis of the entire coding region of the p73 gene revealed previously reported polymorphisms in four MCCs. In one MCC tumour, a mis-sense mutation located in the NH2-terminal transactivation region of the p73 gene was found. These results show that p73, analogous to neuroblastoma, is infrequently mutated in MCC. This is also the first report in which the role of TP53 in MCC has been investigated by sequencing the entire coding region of TP53. TP53 mis-sense mutations and one non-sense mutation were detected in three of 15 examined MCCs, suggesting that TP53 mutations may play a role in the pathogenesis or progression of a subset of MCCs. Moreover, typical UVB induced C to T mutations were found in one MCC cell line thus providing further evidence for sun-exposure in the aetiology of this rare skin cancer.
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PMID:Mutation analysis of P73 and TP53 in Merkel cell carcinoma. 1073 53

Recent studies have demonstrated that angiogenesis and suppressed cell-mediated immunity (CMI) play a central role in the pathogenesis of malignant disease facilitating tumour growth, invasion and metastasis. In the majority of tumours, the malignant process is preceded by a pathological condition or exposure to an irritant which itself is associated with the induction of angiogenesis and/or suppressed CMI. These include: cigarette smoking, chronic bronchitis and lung cancer; chronic oesophagitis and oesophageal cancer; chronic viral infections such as human papilloma virus and ano-genital cancers, chronic hepatitis B and C and hepatocellular carcinoma, and Epstein-Barr virus (EBV) and lymphomas; chronic inflammatory conditions such as Crohn's disease and ulcerative colitis and colorectal cancer; asbestos exposure and mesothelioma and excessive sunlight exposure/sunburn and malignant melanoma. Chronic exposure to growth factors (insulin-like growth factor-I in acromegaly), mutations in tumour suppressor genes (TP53 in Li Fraumeni syndrome) and long-term exposure to immunosuppressive agents (cyclosporin A) may also give rise to similar environments and are associated with the development of a range of solid tumours. The increased blood supply would facilitate the development and proliferation of an abnormal clone or clones of cells arising as the result of: (a) an inherited genetic abnormality; and/or (b) acquired somatic mutations, the latter due to local production and/or enhanced delivery of carcinogens and mutagenic growth factors. With progressive detrimental mutations and growth-induced tumour hypoxia, the transformed cell, to a lesser or greater extent, may amplify the angiogenic process and CMI suppression, thereby facilitating further tumour growth and metastasis. There is accumulating evidence that long-term treatment with cyclo-oxygenase inhibitors (aspirin and indomethacin), cytokines such as interferon-alpha, anti-oestrogens (tamoxifen and raloxifene) and captopril significantly reduces the incidence of solid tumours such as breast and colorectal cancer. These agents are anti-angiogenic and, in the case of aspirin, indomethacin and interferon-alpha have proven immunomodulatory effects. Collectively these observations indicate that angiogenesis and suppressed CMI play a central role in the development and progression of malignant disease.
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PMID:The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease. 1074 Dec 73

Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathogenesis of HBV-induced malignant transformation is, however, incompletely understood. HBx, the protein encoded by the X open reading frame, is a transcriptional activator that has been implicated in hepatocarcinogenesis. HBx inhibits the function of the tumour suppressor protein p53 in what is thought to be an early event in hepatocyte transformation before the later accumulation of inactivating p53 point mutations. HBx inhibits apoptosis but also exerts pro-apoptotic effects. The effects of HBx on apoptosis may be important not only for the development of HCC but also for the establishment of HBV infection. Further implication of HBx in hepatocyte transformation has been the demonstration that it inhibits the repair of damaged hepatocyte DNA. This effect may be mediated by interaction with p53 or through binding to the damaged DNA binding protein (DDB), which plays an accessory role in nucleotide excision repair. In addition, HBx activates cell signalling cascades involving mitogen-activated protein kinase (MAPK) and Janus family tyrosine kinases (JAK)/signal transducer and activators of transcription (STAT) pathways. The implications of these modulating effects of HBx are not fully understood, but they are likely to have wide-ranging effects on hepatocyte proliferation, apoptosis and the regulation of cell growth checkpoints. The cellular functions ascribed to HBx are unusually diverse, and defining the biologically important role of HBx during HBV replication will go some way to understanding the sequelae of chronic HBV infection.
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PMID:Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effects on apoptosis, DNA repair, mitogen-activated protein kinase and JAK/STAT pathways. 1082 73

Gene therapy represents an attractive approach to treat a great variety of diseases, both inherited and acquired, and it is moving slowly from a proof-of-principle phase to a wide application in most medical fields. Liver cancer and viral hepatitis are natural targets for this new therapeutic alternative due to the lack of success of conventional antitumoral and antiviral treatments and the ominous prognosis related with liver tumours. Gene therapy for viral hepatitis is aimed to boost the patient immune response against viral antigens or to make cells resistant to infection by blocking the viral life cycle. Gene transfer techniques applied to the treatment of hepatocellular carcinoma include drug sensitization by suicide genes, genetic immunotherapy, normal tissue protection by transfer of the multidrug resistance gene, replacement of tumour suppressor genes, inhibition of oncogenes and modifications of the biology of the tumour (antiangiogenesis). However, major advances in our understanding of the regulation of gene expression, design of the expression cassettes and development of more efficient gene transfer vectors are mandatory before gene therapy can become a widely used therapeutic modality.
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PMID:Gene therapy of viral hepatitis and hepatocellular carcinoma. 1084 27

The RIZ (PRDM2) locus commonly undergoes loss of heterozygosity (LOH) and maps within the minimal deleted region on 1p36 in hepatocellular carcinoma (HCC). Although peptide-altering mutations of RIZ are rare in HCC, the RIZ1 product is commonly lost in HCC and has tumour suppressive activities. Here, we analysed RIZ gene mutations and LOH in HCC, breast cancer, familial melanoma, colon cancer, and stomach cancer. We found 7 polymorphisms but no mutations. By analysing the Pro704-deletion polymorphism, we detected LOH of RIZ in 31 of 79 (39%) informative HCC cases, 11 of 47 (23%) colon cancer cases, 8 of 43 (19%) breast cancer cases, 8 of 66 (12%) stomach cancer cases. Importantly, loss of the Pro704(+)allele was found in 74% of the 31 LOH positive HCC cases (P< 0.01), indicating a preferential loss and hence a stronger tumour suppressor role for this allele compared to the P704(-)allele. In addition, the Pro704(+)allele was found to be more common in Asians (0.61) than Caucasians (0.42) (P = 0.0000), suggesting an interesting link between gene polymorphisms and potential differences in tumour incidence between racial groups.
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PMID:Preferential loss of a polymorphic RIZ allele in human hepatocellular carcinoma. 1125 86

p53 and p73 proteins activate similar target genes and induce apoptosis and cell cycle arrest. However, p53, but not p73 is considered a tumour-suppressor gene. Unlike p53, p73 deficiency in mice does not lead to a cancer-prone phenotype, and p73 gene is not mutated in human cancers, including hepatocellular carcinoma. Here we report that normal liver cells express only DeltaN-p73 transcript forms giving rise to the synthesis of N-terminally truncated, transcriptionally inactive and dominant negative p73 proteins. In contrast, most hepatocellular carcinoma cells express TA-p73 transcript forms encoding full-length and transcriptionally active p73 proteins, in addition to DeltaN-p73. We also show that together with the acquired expression of TA-p73, the 'retinoblastoma pathway' is inactivated, and E2F1-target genes including cyclin E and p14(ARF) are activated in hepatocellular carcinoma. However, there was no full correlation between 'retinoblastoma pathway' inactivation and TA-p73 expression. Most TA-p73-expressing hepatocellular carcinoma cells have also lost p53 function either by lack of expression or missense mutations. The p73 gene, encoding only DeltaN-p73 protein, may function as a tumour promoter rather than a tumour suppressor in liver tissue. This may be one reason why p73 is not a mutation target in hepatocellular carcinoma.
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PMID:Acquired expression of transcriptionally active p73 in hepatocellular carcinoma cells. 1152 99

Hepatocellular carcinoma (HCC) is one of the most frequent-occurring malignant tumours worldwide, but molecular changes of tumour DNA, with the exception of viral integrations and p53 mutations, are poorly understood. In order to search for common macro-imbalances of genomic tumour DNA, 21 HCCs and 3 HCC-cell lines were characterized by comparative genomic hybridization (CGH), subsequent database analyses and in selected cases by fluorescence in situ hybridization (FISH). Chromosomal subregions of 1q, 8q, 17q and 20q showed frequent gains of genomic material, while losses were most prevalent in subregions of 4q, 6q, 13q and 16q. Deleted regions encompass tumour suppressor genes, like RB-1 and the cadherin gene cluster, some of them previously identified as potential target genes in HCC development. Several potential growth- or transformation-promoting genes located in chromosomal subregions showed frequent gains of genomic material. The present study provides a basis for further genomic and expression analyses in HCCs and in addition suggests chromosome 4q to carry a so far unidentified tumour suppressor gene relevant for HCC development.
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PMID:Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis. 1153 Dec 55

Adenomatous polyposis coli (APC) is mutated in most colorectal cancers. APC downregulates nuclear beta-catenin, which is thought to be critical for its tumour suppressor function. However, APC may have additional and separate functions at the cell periphery. Here, we examine polarized MDCK and WIF-B hepatoma cells and find that APC is associated with their lateral plasma membranes. This depends on the actin cytoskeleton but not on microtubules, and drug wash-out experiments suggest that APC is delivered continuously to the plasma membrane by a dynamic actin-dependent process. In polarized MDCK cells, APC also clusters at microtubule tips in their basal-most regions. Microtubule depolymerization causes APC to relocalize from these tips to the plasma membrane, indicating two distinct peripheral APC pools that are in equilibrium with each other in these cells. Truncations of APC such as those found in APC mutant cancer cells can neither associate with the plasma membrane nor with microtubule tips. The ability of APC to reach the cell periphery may thus contribute to its tumour suppressor function in the intestinal epithelium.
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PMID:Actin-dependent membrane association of the APC tumour suppressor in polarized mammalian epithelial cells. 1168 33

The INK4a-ARF (CDKN2A)- locus on chromosome 9p21 encodes for two tumour suppressor proteins, p16(INK4a) and p14(ARF), that act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway in tumorigenesis of hepatocellular carcinoma (HCC), we analysed the alterations of p14(ARF), p16(INC4a) and p53. After microdissection, DNA of 71 hepatocellular carcinomas was analysed for INK4-ARF inactivation and p53 mutation by DNA sequence analysis, methylation-specific PCR (MSP), restriction-enzyme related polymerase chain reaction (RE-PCR), mRNA expression and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INC4a) were assessed by differential PCR. Inactivation of p14(ARF) was found in 11/71 cases (15%), alterations of p16(INK4a) occurred in 47/71 carcinomas (66%), which correlated with loss of mRNA transcription. Five tumours (7%) had homozygous deletions of the INK4a-ARF locus. We failed to detect specific mutations of both exons. P16(INK4a) methylation with an unmethylated p14(ARF) promotor appeared in 39 cases. Mutations of p53 were found in 30 of 71 HCC (42%), and only one of them harboured p14(ARF) inactivation. We failed to establish alterations of the INK4a-ARF locus or p53 status as independent prognostic factor in these tumours. Our data indicate, that p14(ARF) methylation occurs independently of p16(INK4a) alterations in a subset of HCC together with wild type p53. The INK4a-ARF-/p53-pathway was disrupted in 86% of HCC, either by p53 mutations or by INK4a-ARF inactivation, and may have co-operative effects in hepatocarcinogenesis.
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PMID:INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. 1170 35


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