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)

In the present study, we analysed 34 de novo diffuse large B cell lymphoma (DLCL) from a population-based lymphoma registry for alterations of the RB1 pathway at the genetic (RB1 and CDK4) and protein (pRb, cyclin D1, cyclin D3, CDK4, and E2F-1) level. The results were correlated with the data from our previous studies of CDKN2A deletion and hypermethylation, other p53 pathway components, p27Kip1 expression, and proliferation, as well as with clinical outcome, including prognosis. We found aberrant pRb expression in four (12%) of 34 DLCLs. One of these had a point mutation in intron 3 10 bp downstream of exon 3 generating a novel splice signal. Seven tumours (21%) showed cyclin D3 overexpression, including all three thyroid lymphomas (P = 0.006). Cyclin D3 overexpression and p16INK4A/pRb aberrations were mutually exclusive, supporting an oncogenic role for cyclin D3 in DLCL. p16INK4A inactivation, cyclin D3 overexpression, or aberrant pRb expression was identified in 18 of 34 DLCLs (53%). Combining these results with our previous p53 pathway studies showed that 82% of the de novo DLCLs had alterations of these pathways, and that both pathways were altered in 13 cases (38%). Low E2F-1 expression was associated with treatment failure (P = 0.020), and multivariate analysis of overall survival identified both low E2F-1 expression (relative risk = 6.9; P = 0.0037) and p16INK4A inactivation (relative risk = 3.3; P = 0.0247) as independent prognostic markers. These data support a role of E2F-1 as tumour suppressor gene in lymphoma and strongly suggest that the RB1 and p53 pathways are important in the development of de novo DLCL. Furthermore, low E2F-1 expression and p16INK4A inactivation may serve as prognostic markers for patients with this type of lymphoma.
 ...
PMID:Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A. 1080 23

Recent studies have revealed the evidence for the significance of SV40 genome in human malignancies. In this paper, the presence of SV40-like sequences was investigated in 54 Japanese osteosarcomas in which mutations of the retinoblastoma (Rb), p53, MDM2, and CDK4 genes had been already analysed. Using polymerase chain reaction and Southern hybridization, SV40-like sequences were detected in 25 cases (46.3%). In most cases, only a part of SV40 genome was detected, and the regulatory region containing enhancer sequences was most frequently found (21/54, 38.9%). There was no apparent relationship between the presence of SV40-like sequences and tumour suppressor genes mutations in each tumour. The SV40-like sequences were also detected in peripheral blood cells of substantial proportion of the patients (43.3%), whereas the incidence was much lower (4.7%) in normal healthy controls. This difference is statistically highly significant (P < 0.0001), suggesting that the presence of SV40-like sequences, even if only a part, may play some roles to predispose individuals to osteosarcoma.
 ...
PMID:High incidence of SV40-like sequences detection in tumour and peripheral blood cells of Japanese osteosarcoma patients. 1081 3

p19INK4d, a member of the INK4 family of cyclin-dependent kinase inhibitors, negatively regulates the proto-oncogenic cyclin D/CDK4(6) complexes whose ability to phosphorylate the retinoblastoma tumour suppressor (RB) promotes G1/S transition. In contrast to the related p16INK4a tumour suppressor, expression patterns of 19INK4d in human tissues and tumours remain unknown. As the RB pathway is commonly targeted in cancer, and mouse models suggest a role for p19INK4d in spermatogenesis, we examined the abundance and localization of p19INK4d in the human testis, both during normal development and at various stages of germ-cell tumour pathogenesis. Our data show that the p19INK4d protein is abundant in spermatocytes of normal human adult testes, whereas virtually no p19INK4d is detectable in testicular cancer, including the preinvasive carcinoma in situ stage. Together with the lack of p19INK4d in human foetal germ cells, these results support the concept of foetal origin of the testicular germ-cell tumours, and help better understand the emerging role of the RB pathway in spermatogenesis and tumorigenesis in the human testis. Oncogene (2000) 19, 4146 - 4150
 ...
PMID:Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis. 1096 75

The tumour suppressor gene p16/INK4a encodes a specific inhibitor of the cyclin D-dependent kinases CDK4 and CDK6. p16/INK4a prevents the association of CDK4 with cyclin D1, and subsequently inhibits phosphorylation of retinoblastoma tumour suppressor protein (pRb), thus preventing exit from the G1 phase. In human cancers, the estimated frequency of genetic alteration involving the p16/INK4a locus is believed to be second only to alteration of p53. A high frequency (greater than 50%) of homozygous p16/INK4a gene deletion has been demonstrated in glioblastoma tissues and p16/INK4a is altered in 80% of glioma cell lines. Therefore, restoration of p16/INK4a would suppress cell proliferation and induce cell growth arrest. We showed here that restoration of p16/INK4a expression in p16 negative U87MG, U251MG and partially deleted U373MG by Ad-CMV-p16/INK4a induced growth suppression in vitro and in vivo. Expression of p16 transferred by Ad-CMV-p16/INK4a in glioma cells was highly efficient and maintained for more than seven days. In addition, we found that the endogenous status of p16 and Rb might affect the expression of exogenous p16/INK4a gene and inhibitory effect of cell proliferation. Even though, there were several factors affecting the efficiency of Ad-CMV-p16/INK4 gene transfer, our results suggest that Ad-CMV-p16 gene therapy strategy is potentially useful and warrants further clinical investigation for the treatment of gliomas.
 ...
PMID:Growth inhibitory effect on glioma cells of adenovirus-mediated p16/INK4a gene transfer in vitro and in vivo. 1102 24

The retinoblastoma (pRb)-related p130 pocket protein is a regulator of cell growth and differentiation, and a candidate tumour suppressor. Both pRb and p130 operate through interactions with cellular proteins, including the E2F transcription factors. While such interactions are controlled by phosphorylation of multiple sites of pRb, regulation of p130 remains poorly understood. We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [Cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. When expressed in U2OS cells, the phosphorylation-deficient mutant p130(Delta)(CDK4), in which the Cdk4 specific sites were mutated to alanine residues, imposed a more sustained G1 arrest than a constitutively active pRb(Delta)(CDK), known to repress all cellular E2F activity. Experiments using p130(Delta)(Cdk4) and another phosphorylation-deficient mutant, p130(PM19A), with 19 phosphorylation sites mutated, revealed that the p130-imposed G1 block reflects cooperative growth-suppressive effects of phosphorylation-regulated E2F binding and phosphorylation-independent sequestration of cyclin E(A)-Cdk2 through the N-terminal cyclin binding motif of p130.
 ...
PMID:Phosphorylation-dependent and -independent functions of p130 cooperate to evoke a sustained G1 block. 1115 49

Nineteen specimens from primary human malignant mesotheliomas obtained from 19 patients were screened for activating point mutations in the oncogenes N-ras and CDK4 by combined RFLP-PCR/SSCP analysis. In addition, all tumours were screened for deletions and point mutations in the tumour suppressor genes p53, p16INK4a (CDKN2A) and p14ARF (exon-1beta) by combined multiplex-PCR/SSCP analysis. No mutations were found in N-ras, p53 and CDK4. Three tumours displayed homozygous deletion (co-deletion of exons 1, 2 and 3) of p16INK4a. One of them displayed additional homozygous deletion of p14ARF (exon-1beta). Two silent point mutations and 2 polymorphisms were found in p16INK4a in 3 tumours. Our preliminary data indicate that disarrangement of the Rb1 pathway may be involved in mesothelioma formation.
 ...
PMID:Mutational analysis of N-ras, p53, p16INK4a, p14ARF and CDK4 genes in primary human malignant mesotheliomas. 1117 13

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.
 ...
PMID:INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. 1170 35

To date, two genes have been implicated in melanoma pathogenesis. The first, CDKN2A, is a tumour suppressor gene with germline mutations detected in 20% of melanoma-prone families. The second, CDK4, is an oncogene with co-segregating germline mutations detected in only three kindreds worldwide. We examined 16 American melanoma-prone families for mutations in all coding exons of CDK4 and screened additional members of two previously reported families with the Arg24Cys germline CDK4 mutation to evaluate the penetrance of the mutation. No new CDK4 mutations were identified. In the two Arg24Cys families, the penetrance was estimated to be 63%. Overall, 12 out of 12 invasive melanoma patients, none out of one in situ melanoma patient, five out of 13 dysplastic naevi patients, two out of 15 unaffected family members, and none out of 10 spouses carried the Arg24Cys mutation. Dysplastic naevi did not strongly co-segregate with the Arg24Cys mutation. Thus the phenotype observed in melanoma-prone CDK4 families appears to be more complex than just the CDK4 mutation. Both genetic and environmental factors are likely to contribute to the occurrence of melanoma and dysplastic naevi in these families. In summary, although CDK4 is a melanoma susceptibility gene, it plays a minor role in hereditary melanoma.
 ...
PMID:Rarity of CDK4 germline mutations in familial melanoma. 1182 58

Supratentorial primitive neuroectodermal tumours (sPNETs) are malignant central nervous system tumours of childhood which are histologically characterized by poorly differentiated neuroepithelial cells with the capacity for divergent differentiation into glial, neuronal, myogenic or melanotic lines. The histological differential diagnosis between sPNET and glioblastoma multiforme (GBM) may be difficult, particularly as GBMs can sometimes demonstrate a poorly differentiated PNET-like phenotype. To identify molecular genetic markers that may distinguish sPNET and GBM, we investigated 12 cerebral sPNETs and six GBMs from paediatric patients for genetic alterations of the TP53, PTEN, CDKN2A, EGFR, CDK4 and MDM2 genes, as well as for allelic loss on chromosome arms 10q and 17p. Mutations of the TP53 tumour suppressor gene were found in one of 12 sPNETs (8%) and two of six GBMs (33%). None of the sPNETs but two of six GBMs (33%, including one GBM with a TP53 mutation) showed allelic losses on chromosome arm 17p. PTEN mutations were detected in one of 12 sPNET (8%) and one of six GBMs (17%). None of the sPNETs and GBMs carried a homozygous deletion involving the CDKN2A tumour suppressor gene. No amplification of the EGFR, CDK4 or MDM2 proto-oncogenes was detected. Taken together, our results indicate that paediatric GBMs differ from sPNETs by a higher incidence of allelic losses on 17p and TP53 mutations. In addition, the patterns of genetic alterations in sPNETs and paediatric GBMs appear to be distinct from those in cerebellar medulloblastomas and adult GBMs, respectively.
 ...
PMID:Molecular genetic analysis of the TP53, PTEN, CDKN2A, EGFR, CDK4 and MDM2 tumour-associated genes in supratentorial primitive neuroectodermal tumours and glioblastomas of childhood. 1217 45

Pleomorphic adenomas of the parotid gland are benign tumours composed of epithelial and mesenchymal cells. The INK4a-ARF (CDKN2A) locus on chromosome 9p21 encodes two tumour suppressor proteins, p16(INK4a) and p14(ARF), which act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway in pleomorphic adenomas, this study analysed alterations of p14(ARF), p16(INK4a), p53, and pRb in these tumours. After microdissecting the different histological components, 42 pleomorphic adenomas of the parotid gland were analysed for INK4a-ARF inactivation by DNA sequence analysis, methylation-specific PCR (MSP), restriction enzyme-related polymerase chain reaction (RE-PCR), mRNA expression, microsatellite analysis, and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INK4a) were assessed by differential PCR. The status of p53 and Rb was examined by direct sequencing and immunohistochemistry. Using microdissection, it was possible to examine the tumour components, i.e. epithelial, mesenchymal, and transitional, separately after immunohistochemical identification. Methylation of p14(ARF) was found in 1/42 cases and alterations of p16(INK4a) occurred in 12/42 of pleomorphic adenomas, which correlated with loss of mRNA transcription. Microdeletions or specific mutations of either exon were not detected. Methylation was detected exclusively in the epithelial and transitional components and not within the mesenchymal part of the tumour. p53 mutations were detected in 4/42 adenomas, also occurring solely in the epithelial components of the tumours. pRb was detected immunohistochemically in 40/42 adenomas. In normal, corresponding parotid tissue, p14(ARF), p16(INK4a), p53, and pRb alterations were not observed. The observation that alterations of p14(ARF) and p16(INK4a), and also p53 mutations, occurred exclusively in the epithelial and transitional components of pleomorphic adenoma supports the theory that these areas are prone to malignant transformation to carcinoma in adenoma.
 ...
PMID:Alterations of the INK4a-ARF gene locus in pleomorphic adenoma of the parotid gland. 1237 65


<< Previous 1 2 3 4 Next >>