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)

The human cdk2/cyclin A kinase complex is a key regulator of the events of S phase. This complex contains several proteins involved in regulating its catalytic activity, including one or more of the CKS proteins, which have recently been shown to inhibit the activation of the cdk2 kinase. To investigate whether the CKS genes may be altered in human neoplasia, we mapped the chromosome locations of CKS1 and CKS2 by fluorescence in situ hybridization (FISH). CKS1 was localized to 8q21, a locus that is seldom grossly altered in cancer. The localization of CKS2 to 9q22 places it very near to a putative tumour suppressor locus suggested to be responsible for susceptibility to the Basal Cell Nervus Syndrome (BCNS or Gorlin's syndrome) familial cancer disorder. Six fibroblast cell lines isolated from patients with BCNS were demonstrated by FISH to have both copies of CKS2 present. Partial sequencing of a genomic clone of CKS2 revealed that the open reading frame lies over three exons. Examination of the six cell lines by SSCP and PCR-based sequencing of the parts of the three exons coding for the full length protein demonstrated no consistent divergence from the reported cDNA sequence in any exon. It is unlikely that CKS2 is the BCNS tumour suppressor gene.
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PMID:Chromosomal mapping of the human genes CKS1 to 8q21 and CKS2 to 9q22. 869 18

Basal cell carcinoma (BCC) is the most common cancer in humans. The majority of sporadic BCCs have allele loss on chromosome 9q22 implying that inactivation of a tumour suppressor in this region is an important step in BCC formation. The gene for nevoid basal cell carcinoma syndrome (NBCCS), an autosomal dominant disorder characterized by multiple BCCs, maps to the same region and is presumed to be the tumour suppressor inactivated at this site. NBCCS has been identified recently and encodes a protein with strong homology to the Drosophila segment polarity gene, patched. Analysis of Drosophila mutants indicates that patched interacts with the hedgehog signalling pathway, repressing the expression of various hedgehog target genes including wingless, decapentaplegic and patched itself. Using single strand conformational polymorphism (SSCP) to screen human patched in 37 sporadic BCCs, we detected mutations in one-third of the tumours. Direct sequencing of two BCCs without SSCP variants revealed mutations in those tumours as well suggesting that inactivation of patched is probably a necessary step in BCC development. Northern blots and RNA in situ hybridization showed that patched is expressed at high levels in tumour cells but not normal skin suggesting that mutational inactivation of the gene leads to overexpression of mutant transcript owing to failure of a negative feedback mechanism.
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PMID:The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. 878 9

The cloning of vertebrate homologues of the Drosophila segment polarity gene patched has led to confirmation of a role for the multipass transmembrane protein which it encodes as a receptor for secreted signalling proteins of the Hedgehog family. In addition, human patched has been identified as a tumour suppressor gene implicated in basal cell carcinomas and medullablastomas.
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PMID:The patched gene in development and cancer. 952 11

The hedgehog signalling pathway plays a vital role in Drosophila embryonic patterning and development. Hedgehog is a secreted protein, unrelated to classical growth factors, which seems to form concentration gradients across those tissues involved in pattern formation. Cloning of vertebrate homologues of hedgehog and other genes has illustrated the remarkable conservation of function of this pathway throughout evolution. The human homologue of patched, a receptor for the hedgehog protein, was cloned as the gene responsible for naevoid basal cell carcinoma syndrome (NBCCS/'Gorlin Syndrome'), an autosomal dominant condition in which patients suffer from multiple basal cell carcinomas and a wide spectrum of developmental abnormalities. Its role as a tumour suppressor gene in both NBCCS and sporadic basal cell carcinoma led to the suggestion that mutation or inactivation of human patched may be an essential step in development of basal cell carcinomas and other skin tumours. This review describes our current understanding of hedgehog signalling in Drosophila and vertebrates and its relation to the development of human basal cell carcinoma and other skin tumours, together with a discussion of future avenues of research into this critical and intriguing pathway.
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PMID:The hedgehog signalling pathway and its role in basal cell carcinoma. 1072 88

The nevoid basal cell carcinoma syndrome is an autosomal dominant disorder characterized by multiple cutaneous basal cell carcinomas, jaw keratocysts and a variety of other tumours, and developmental abnormalities. Recently, this syndrome was shown to result from germ line mutations in human patched(PTC) gene, which encodes a membrane receptor and functions as an important developmental regulator and a tumour suppressor. Haploinsufficiency for the PTC locus is likely to give rise to developmental abnormalities characterized by symmetrical defects and malformed spine and ribs. Postnatal loss of the normal PTC allele leads to multiple basal cell carcinomas and other cancers. PTC mutations and loss of the remaining wild-type allele have also been identified in sporadic basal cell carcinomas and meduloblastomas.
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PMID:[Nevoid basal cell carcinoma syndrome]. 1092 8

Glandular odontogenic cyst (GOC) is a rare jawbone cyst of odontogenic origin. Human patched (PTCH) is a tumour suppressor gene that has been recently associated with signalling pathways during odontogenesis. Recently alterations of this gene were found on sporadic odontogenic keratocysts. This evidence, together with the biological behaviour similarities of both lesions, and the absence of reports on molecular analysis of GOC, led us to hypothesize that PTCH gene mutations may underlie the tumorigenesis of GOC. Therefore the aim of this study was to report one additional case of GOC and investigate the PTCH gene of the cyst. No mutations were found in the splicing and coding regions of the PTCH gene. In conclusion, the PTCH gene does not seem to be involved in GOC pathogenesis.
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PMID:Glandular odontogenic cyst: absence of PTCH gene mutation. 1116 58

The odontogenic keratocyst (OKC) is a clinic and histologically distinct form of odontogenic cyst. It is known for its aggressive behaviour, high recurrence rate and may be in association with nevoid basal cell carcinoma syndrome. Recently was reported that the lost of human patched (ptch), a tumour suppressor gene, is the possible molecular origin of the OKC. This report reviews the clinic, histologic and molecular characteristics of OKCs. Treatment and recurrence are discussed too.
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PMID:New considerations about the diagnosis of odontogenic keratocyst. 1169 68

Studies of the HEDGEHOG signalling pathway in Drosophila have revealed a functional link between two genes, cubitus interruptus and patched, whose human homologues are, respectively, a proto-oncogene and a tumour suppressor. While the former has been implicated as a transcription factor, controversy has surrounded the function of the transmembrane protein encoded by the latter. Somewhere in the signal-transduction pathway between these two lies protein kinase A (PKA), and now SMOOTHENED, whose similarity to G-protein-coupled receptors suggests a link with PKA, has also been implicated in the pathway. This article summarizes the current understanding of the pathway and the interactions between these proteins.
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PMID:'Smoothening' the path for hedgehogs. 1515

Basal cell carcinoma is the most common human malignancy in populations of European origin, and Australia has the highest incidence of basal cell carcinoma in the world. Great advances in the understanding of the genetics of this cancer have occurred in recent years. Mutations of the patched 1 gene (PTCH1) lead to basal cell carcinoma predisposition in Gorlin syndrome. PTCH1 is part of the hedgehog signalling pathway, and derangements within this pathway are now known to be important in the carcinogenesis of many different cancers including sporadic basal cell carcinoma. The molecular biology of the hedgehog pathway is discussed, and mouse models of basal cell carcinoma based on this pathway are explored. New developments in non-surgical treatment of basal cell carcinoma are based on this knowledge. Other genes of importance to basal cell carcinoma development include the tumour suppressor gene P53 and the melanocortin-1 receptor gene. In addition, we discuss molecules of possible importance such as the glutathione-S-transferases, DNA repair genes, cyclin-dependent kinase inhibitor 2A, Brahma and connexins. Evidence of familial aggregation of this cancer is explored and supports the possibility of genetic predisposition to this common malignancy.
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PMID:Genetics of basal cell carcinoma. 2054 11

We have previously reported that the expression of the CL2/CCDC80 gene is downregulated in human papillary thyroid carcinomas, particularly in follicular variants. We have also reported that the restoration of CL2/CCDC80 expression reverted the malignant phenotype of thyroid carcinoma cell lines and that CL2/CCDC80 positively regulated E-cadherin expression, an ability that likely accounts for the role of the CL2/CCDC80 gene in thyroid cancer progression. In order to validate the tumour suppressor role of the CL2/CCDC80 gene in thyroid carcinogenesis we generated cl2/ccdc80 knock-out mice. We found that embryonic fibroblasts from cl2/ccdc80(-/-) mice showed higher proliferation rate and lower susceptibility to apoptosis. Furthermore, cl2/ccdc80(-/-) mice developed thyroid adenomas and ovarian carcinomas. Finally, ret/PTC1 transgenic mice crossed with the cl2/ccdc80 knock-out mice developed more aggressive thyroid carcinomas compared with those observed in the single ret/PTC1 transgenic mice. Together, these results indicate CL2/CCDC80 as a putative tumour suppressor gene in human thyroid carcinogenesis.
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PMID:The cl2/dro1/ccdc80 null mice develop thyroid and ovarian neoplasias. 2549 69


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