Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P43146 (tumour suppressor)
5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By 1927 for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), and by 1955 for melanoma, the broad grounds for relating sun exposure to skin cancer had been established: that these are more frequent in residents of areas of high ambient solar irradiance, are more frequent in sun-sensitive people, occur mainly on sun-exposed body sites, are more frequent in people with high sun exposure, and are more frequent in people with benign sun-related skin conditions. The past 40 years have added both quantity and quality to the epidemiological evidence and, most recently, provided direct evidence that sun exposure is the cause of mutations in critical tumour suppressor genes in BCC, SCC and melanoma. Complete or more convincing answers are still needed to many questions of detail. They include whether the pattern of sun exposure is really important in, and acts independently of amount of sun exposure in, affecting the risk of melanoma and BCC; what the shape of the relationship between the amount of sun exposure and risk of BCC and melanoma is when the pattern of exposure is held constant; whether there really is a plateau in risk of BCC and melanoma beyond some level of the amount of exposure; whether this exposure-response relationship depends on cutaneous sensitivity to the sun and in what way; whether sunburn makes a specific contribution to the risk of skin cancer independent of the amount of sun exposure; whether sun exposure close to the time of diagnosis of skin cancer contributes anything to the development of the cancer; what the solar radiation action spectrum is for each kind of skin cancer; and whether sunscreens are effective in protecting against skin cancer.
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PMID:Sun exposure and skin cancer. 1099 63

Approximately 10% of human cutaneous melanoma cases occur in families with the familial atypical multiple mole melanoma (FAMMM) syndrome, which is characterised by the familial occurrence of melanomas and atypical precursor naevi. A melanoma-associated gene has been mapped to 9p2l, encoding for the tumour suppressor gene CDKN2A. Worldwide, germline mutations in melanoma kindreds implicate this cell cycle regulator (p16) as a susceptibility gene for malignant melanoma. Most FAMMM families registered at the Leiden Pigmented Lesions Clinic share the same CDKN2A inactivating deletion (P16-Leiden). Presymptomatic DNA diagnosis will now be available for P16-Leiden positive FAMMM family members at the Leiden University Medical Centre.
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PMID:[From gene to disease; from p16 to melanoma]. 1110 70

The chromosome 9p21 region has been described to be frequently deleted in several neoplasias. The cyclin dependent kinase inhibitor 2A (CDKN2A or P16) gene was cloned in this region and identified as a tumour suppressor gene. However, much evidence indicates the existence of another tumour suppressor gene located proximal to the CDKN2A gene, which could be involved in cutaneous malignant melanoma (CMM) initiation. In the present report we have further investigated this 9p21 chromosomal region and cloned and characterised a novel gene within it (C9orf11). This gene shares no similarities to any known gene or predicted protein representing a novel human gene. Nevertheless, a putative leucine zipper pattern is located at the C-terminal end of the predicted protein, suggesting that it could dimerise. C9orf11 encodes for a protein of 294 amino acids with a predicted molecular mass of 32.8 kDa. C9orf11 is organised in eight exons that encompass a region of approx. 13 kb. Expression analysis demonstrates that C9orf11 is highly expressed in testis, although minor expression was seen in other tissues. Mutations in the C9orf11 gene were not detected in CMM families that were negative for CDKN2A mutations. Two SNPs for the C9orf11 gene have been identified, which could be used in segregation or association studies for other disorders.
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PMID:Isolation and characterisation of a novel human gene (C9orf11) on chromosome 9p21, a region frequently deleted in human cancer. 1111 25

The melanoma-astrocytoma syndrome is characterized by a dual predisposition to melanoma and neural system tumours, commonly astrocytoma. Germline deletions of the region on 9p21 containing the CDKN2A and CDKN2B genes and CDKN2A exon 1beta have been reported in kindreds, implicating contiguous tumour suppressor gene deletion as a cause of this syndrome. We describe a family characterized by multiple melanoma and neural cell tumours segregating with a germline deletion of the p14(ARF)-specific exon 1beta of the CDKN2A gene. This deletion does not affect the coding or minimal promoter sequences of either the CDKN2A or CDKN2B genes. Our results are consistent with either: (i) loss of p14(ARF) function being the critical abnormality associated with this syndrome, rather than contiguous loss of both the CDKN2A and CDKN2B genes as suggested previously; or (ii) disruption of expression of p16 by mechanisms as yet unknown.
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PMID:A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. 1113 14

Bcl-2 family member proteins are differentially expressed in skin and in non-melanoma skin cancer (NMSC). To elucidate the contribution of bcl-2 and bax proteins to epidermal differentiation and skin carcinogenesis, we investigated keratinocyte proliferation, differentiation and tumourigenesis in bcl-2(-/-) and bax(-/-) mice. The rate and pattern of proliferation and spontaneous cell death in the bcl-2(-/-) and bax(-/-) mice were not different from control mice. The epidermis of bcl-2(-/-) and bax(-/-) expressed sightly higher levels of cytokeratin 1 and loricrin compared to control littermates. The apoptotic response to ultraviolet-induced genotoxic stress was assessed by quantitating TUNEL positive cells. Bax(-/-) keratinocytes showed a significant resistance to UV-induced cell death compared to control mice. The life-span of bcl-2(-/-) mice precluded an assessment of bcl-2 gene disruption on in vivo tumourigenesis. A significant increase in tumour incidence was observed in bax(-/-) mice compared to control mice in two-step chemical carcinogenesis studies. These findings suggest that bcl-2 and bax gene products may be important determinants of normal keratinocyte differentiation and response to genotoxic stress in vivo, and indicate that bax may provide a tumour suppressor effect during skin carcinogenesis.
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PMID:Bax gene disruption alters the epidermal response to ultraviolet irradiation and in vivo induced skin carcinogenesis. 1117

Gene therapy was initially thought of as a means to correct single gene defects in hereditary disease. In the meantime, cancer has become by far the most important indication for gene therapy in clinical trials. In the foreseeable future, the best way to achieve reasonable intratumoral concentrations of a transgene with available vectors is direct intratumoral injection with or without the aid of various techniques such as endoscopy or CT-guidance. At present, viral and non-viral methods of gene transfer are used either in vivo or ex vivo/in vitro. The most important viral vectors currently in use in clinical trials comprise retroviruses, adenoviruses, adeno-associated viruses, and herpes viruses. None of the available vectors satisfies all the criteria of an ideal gene therapeutic system, and vectors with only minimal residues of their parent viruses ("gutless vectors") as well as completely "synthetic viral vectors" will gain more and more importance in the future. Non-viral gene therapy methods include liposomes, injection of vector-free DNA ("naked DNA"), protein-DNA complexes, delivery by "gene gun," calcium-phosphate precipitation, electroporation, and intracellular microinjection of DNA. The first clinical trial of gene therapy for cancer was performed in 1991 in patients with melanoma, and since then more than 5000 patients have been treated worldwide in more than 400 clinical protocols. With the exception of a case of fatal toxicity in a young man with hereditary liver disease treated intrahepatically with high doses of adenovirus, side effects have been rare and usually mild in all these studies and expression of the transgene could be demonstrated in patients in vivo. However, despite anecdotal reports of therapeutic responses in some patients, unequivocal proof of clinical efficacy is still lacking for most of the varied approaches to gene therapy in humans. As well as our only fragmentary understanding of the molecular pathophysiology of many diseases, the principal reason for the present lack of clinical success of gene therapy is the very low transduction and expression efficiency in vivo of available vectors. Despite the complexities of gene therapy for cancer, the numerous different approaches can be subdivided into three basic concepts: (1) strengthening of the immune response against a tumour, (2) repair of cell cycle defects caused by losses of tumour suppressor genes or inappropriate activation of oncogenes, and (3) suicide gene strategies. In addition, the importance of gene marker studies and gene therapeutic protection of normal tissue are briefly covered in this review.
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PMID:Gene therapy of cancer. 1120 84

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

Chromosomal region 11q22-q23 is a frequent target for deletion during the development of many solid tumour types, including breast, ovary, cervix, stomach, bladder carcinomas and melanoma. One of the most commonly deleted subregions contains the SDHD gene, which encodes the small subunit of cytochrome b (cybS) in mitochondrial complex II (succinate-ubiquinone oxidoreductase). Germline mutations in SDHD cause hereditary paraganglioma type 1 (PGL1), and suggest a tumour suppressor role for cybS. We present a high-resolution physical map spanning SDHD, covered by 19 YACs and 20 BACs. An approximate 1.1-Mb gene-rich region around SDHD is spanned by a complete BAC contig. Twenty-six new STSs are developed from the BAC clone ends. In addition to the discovery and characterisation of 15 new simple tandem repeat polymorphisms, we provide integrated positional information for 33 ESTs and known genes, including KIAA1391, POU2AF1 (OBF1), PPP2R1B, CRYAB, HSPB2, DLAT, IL-18, PTPS, KIAA0781 and KAIA4591, which is mapped by NotI site cloning. We describe full-length transcript sequence for PPP2R1B, encoding the protein phosphatase 2A regulatory subunit A beta isoform. We also discover a processed pseudogene for USA-CYP, a cyclophilin associated with U4/U6 snRPNs, and a novel gene, DDP2, encoding a mitochondrial protein similar to the X-linked deafness-dystonia protein, which is juxtaposed 5'-to-5' to SDHD. This map will help assess this gene-rich region in PGL and in other common tumours.
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PMID:A high-resolution integrated map spanning the SDHD gene at 11q23: a 1.1-Mb BAC contig, a partial transcript map and 15 new repeat polymorphisms in a tumour-suppressor region. 1131 45

MIA (melanoma inhibitory activity) has been previously isolated from the tissue culture supernatant of melanoma cell lines as an autoregulatory activity, inhibiting thymidine incorporation. However, subsequent analyses of melanocytic tumours in vivo have correlated enhanced MIA expression with progression of melanocytic tumours, conflicting with the idea that MIA acts as a tumour suppressor. To investigate the role of MIA in vivo, we have therefore generated a panel of stably transfected B16 cell clones secreting different amounts of MIA. The capacity of these cell clones to form lung metastases in syngeneic C57Bl6 mice was strictly correlated to the level of MIA secretion, but the clones did not differ with respect to their proliferation in vitro. In summary, we suggest that MIA plays a causal role in promoting the metastasis of malignant melanomas, involving inhibition of tumour cell attachment to extracellular matrix molecules within their local milieu.
Melanoma Res 2001 Aug
PMID:Functional role of melanoma inhibitory activity in regulating invasion and metastasis of malignant melanoma cells in vivo. 1147 31

The INK4a/ARF locus encodes the cyclin dependent kinase inhibitor, p16(INK4a) and the p53 activator, p14ARF. These two proteins have an independent first exon (exon 1alpha and exon 1beta, respectively) but share exons 2 and 3 and are translated in different reading frames. Germline mutations in this locus are associated with melanoma susceptibility in 20-40% of multiple case melanoma families. Although most of these mutations specifically inactivate p16(INK4a), more than 40% of the INK4a/ARF alterations located in exon 2, affect both p16(INK4a) and p14ARF. We now report a 16 base pair exon 1beta germline insertion specifically altering p14ARF, but not p16(INK4a), in an individual with multiple primary melanomas. This mutant p14ARF, 60ins16, was restricted to the cytoplasm, did not stabilize p53 and was unable to arrest the growth of a p53 expressing melanoma cell line. This is the first example of an exon 1beta mutation that inactivates p14ARF, and thus implicates a role for this tumour suppressor in melanoma predisposition.
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PMID:A melanoma-associated germline mutation in exon 1beta inactivates p14ARF. 1157 53


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