Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CDKN2A and CDKN2B genes, encoding p16 and p15 respectively, are located on chromosome 9p21, a locus at which frequent homozygous and heterozygous deletions occur in many primary human tumors, including esophageal carcinoma. CDKN2A and CDKN2B inhibit cyclin dependent kinase 4 (CDK4) and CDK6 and control cellular proliferation by preventing entry into the S phase of the cell cycle. Their inactivation may contribute to uncontrolled growth in human cancer. We previously described CDKN2A exon 2 mutations in a pilot study of 43 esophageal cancers. In order to determine whether CDKN2A and CDKN2B are frequent targets of 9p21 deletion in esophageal carcinogenesis, we have now analyzed 60 primary esophageal cancers for mutations in both exons 1 and 2 of CDKN2A and CDKN2B by direct sequencing of PCR amplified genomic DNAs. In conjunction with our previously published data, we have identified a total of eight nucleic acid substitutions among 60 esophageal carcinomas; here, we describe one new CDKN2B nonsense mutation and one new silent CDKN2B mutation that occurred somatically. Taken together, these results suggest that intragenic mutations in CDKN2A and CDKN2B occur in esophageal cancer, but that they are infrequent events. In view of the known high frequency of loss of heterozygosity at the chromosome 9p21 locus in esophageal cancers, the current data suggest that intragenic mutation is not the predominant mode of inactivation of CDKN2A and CDKN2B or that other genes are targets of deletion at this locus in these cancers.
Hum Mol Genet 1995 Oct
PMID:Intragenic mutations of CDKN2B and CDKN2A in primary human esophageal cancers. 859 11

CDKN2A, the gene encoding the cell-cycle inhibitor p16CDKN2A, was first identified in 1994. Since then, somatic mutations have been observed in many cancers and germline alterations have been found in kindreds with familial atypical multiple mole/melanoma (FAMMM), also known as atypical mole syndrome. In this review we tabulate the known mutations in this gene and discuss specific aspects, particularly with respect to germline mutations and cancer predisposition.
Mol Med 1997 Jan
PMID:The CDKN2A (p16) gene and human cancer. 913 80

The p16INK4A (CDKN2A/MTS1) putative tumor suppressor gene encodes a cyclin dependent kinase inhibitor which plays an important role in the regulation of the G1/S phase cell cycle checkpoint. A high frequency of various p16 gene alterations were consequently observed in many primary tumors. P16 can be inactivated by different mechanisms: i) homozygous deletion, ii) methylation of the promoter region or iii) point mutation. In order to investigate p16 alterations in head and neck cancer (HNC) we analyzed 70 primary tumors of the larynx, pharynx and oral cavity including their corresponding normal mucosa for mutation inactivation by direct sequencing exon 2. We detected only one so far undescribed transversion G to T at position 322 (Asp108Tyr) and a known polymorphism (Ala148Thr) in five cases. The methylation status of the p16 promoter region was analyzed by an improved highly sensitive methylation-specific PCR protocol. P16 methylation inactivation was found in 16 of 55 cases (29%). Our data indicate that p16 point mutations in HNC are less frequent, but inactivation by methylation of the promoter region could be involved in genesis and progression of HNC.
Int J Mol Med 1999 Jul
PMID:Tumor suppressor gene p16 (CDKN2A) mutation status and promoter inactivation in head and neck cancer. 1037 39

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.
Hum Mol Genet 2001 Jan 01
PMID:A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. 1113 14

Germline mutations of CDKN2A at 9p21 have been shown to predispose to disease in melanoma pedigrees worldwide. However, there remains a significant proportion of melanoma pedigrees with evidence of linkage to 9p21 in which mutations in CDKN2A have not been detected. Investigation of other potential tumour suppressor genes at 9p21 and the promotor of CDKN2A has been unable to explain genetic predisposition to melanoma in these pedigrees. Here we describe a mutation, IVS2-105 A/G, deep in intron 2 of CDKN2A, detected in six English melanoma pedigrees. The mutation creates a false GT splice donor site 105 bases 5' of exon 3 and has been demonstrated to result in aberrant splicing of the mRNA. This is the most common mutation identified in English families to date. The presence of this deep intronic mutation in a relatively large number of kindreds, indicates that it may account for a significant proportion of 9p21-linked melanoma pedigrees with no detectable mutations in the coding region of CDKN2A. In addition, the identification of one deep intronic mutation in CDKN2A indicates the possibility of the existence of other similar splicing mutations located elsewhere in the CDKN2A introns.
Hum Mol Genet 2001 Nov 01
PMID:A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees. 1172 55

Familial melanoma predisposition is associated with germline mutations at the CDKN2A/ARF locus in up to 40% of families. The exact role of the two proteins encoded by this complex locus in this predisposition is unclear. Most mutations affect either CDKN2A only or products of both genes. Recently a deletion affecting ARF-specific exon 1beta was reported in a family with melanoma and neural tumours. However, the possibility of this deletion also altering the CDKN2A transcript could not be excluded. More convincingly, a 16 base pair insertion in exon 1beta has been reported in an individual with multiple melanomas suggesting a direct role for ARF in melanoma predisposition. We report here a splice mutation in exon 1beta in a family with melanoma that results in ARF haploinsufficiency. The mutation was observed in a mother and daughter with melanoma. A sibling of the mother with breast cancer also had this mutation. Analysis of the melanoma from one individual revealed a 62 bp deletion in exon 3 of the wildtype allele and loss of the mutant allele; these somatic changes would affect both CDKN2A and ARF. These somatic events suggest that concomitant inactivation of both ARF and CDKN2A may be necessary for melanoma development and that mutations in ARF and CDKN2A possibly confer different levels of susceptibility to melanoma, with the former associated with lesser predisposition. In this situation, the events follow a 'three-hit' model as observed in tumours from FAP patients with an attenuated phenotype. Overall, the data suggest a direct role for ARF haploinsufficiency in melanoma predisposition and co-operation between ARF and CDKN2A in tumour formation, consistent with recent observations in Cdkn2a-specific knockout mice.
Hum Mol Genet 2002 May 15
PMID:Germline mutation of ARF in a melanoma kindred. 1201 8

Multiplex methylation-sensitive PCR was employed in studying the methylation of the RB1 and CDKN2A/p16 promoter regions in 52 retinoblastomas. Aberrant methylation inactivating RB1 was detected in 14 (27%) tumors. Methylation of p16 was for the first time observed in retinoblastoma (9 tumors, 17%). Both promoters proved to be methylated in two tumors. In four tumors, aberrant methylation was combined with structural defects of both RB1 alleles. Aberrant methylation of the p16 promoter was the second mutation event in two tumors and was not accompanied by RB1 defects in one tumor. Complex testing for RB1 mutations, loss of heterozygosity, and functional inactivation of the two genes revealed a molecular defect in at least one allele in 51 (98%) tumors.
Mol Biol (Mosk)
PMID:[RB1 and CDKN2A functional defects resulting in retinoblastoma]. 1239 39

Cyclin-dependent kinase inhibitor p16(INK4a) is the founding member of the INK4 family of tumor suppressors capable of arresting mammalian cell division. Missense mutations in the p16(INK4a) gene (INK4a/CDKN2A/MTS1) are strongly linked to several types of human cancer. These mutations are evenly distributed throughout this small, ankyrin repeat protein and the majority of them disrupt the native secondary and/or tertiary structure, leading to protein unfolding, aggregation and loss of function. We report here the use of multiple stabilizing substitutions to increase the stability of p16(INK4a) and furthermore, to restore Cdk4 binding activity of several defective, cancer-related mutant proteins. Stabilizing substitutions were predicted using four different techniques. The three most effective substitutions were combined to create a hyperstable p16(INK4a) variant that is 1.4 kcal/mol more stable than wild-type. This engineered construct is monomeric in solution with wild-type-like secondary and tertiary structure and cyclin-dependent kinase 4 binding activity. Interestingly, these hyperstable substitutions, when combined with oncogenic mutations R24P, P81L or V126D, can significantly restore Cdk4 binding activity, despite the divergent features of each destabilizing mutation. Extensive biophysical studies indicate that the hyperstable substitutions enhance the binding activity of mutant p16 through several different mechanisms, including an increased amount of secondary structure and thermostability, reduction in exposed hydrophobic surface(s) and/or a reduced tendency to aggregate. This apparent global suppressor effect suggests that increasing the thermodynamic stability of p16 can be used as a general strategy to restore the biological activity to defective mutants of this important tumor suppressor protein.
J Mol Biol 2003 Mar 14
PMID:Design and characterization of a hyperstable p16INK4a that restores Cdk4 binding activity when combined with oncogenic mutations. 1261 25

The classification of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) can pose diagnostic problems due to inter-observer variability and other limitations of histopathology. There is an interest in developing classificatory models of lung neoplasms based on the analysis of multivariate molecular data with statistical methods and/or neural networks. DNA methylation levels at 20 loci were measured in 41 SCLC and 46 NSCLC cell lines with the quantitative real-time PCR method MethyLight. The data were analyzed with artificial neural networks (ANN) and linear discriminant analysis (LDA) to classify the cell lines into SCLC or into NSCLC. Models used either data from all 20 loci, or from five significant DNA methylation loci that were selected by a step-wise back-propagation procedure (PTGS2, CALCA, MTHFR, ESR1, and CDKN2A). The data were sorted randomly by cell line into 10 different data sets, each with training and testing subsets composed of 71 and 16 of the cases, respectively. Ten ANN models were trained using the 10 data sets: five using 20 variables, and five using the five variables selected by step-wise back-propagation. The ANN models with 20 input variables correctly classified 100% of the cell lines, while the models with only five variables correctly classified 87 to 100% of cases. For comparison, 10 different LDA models were trained and tested using the same data sets with either the original data or with logarithmically transformed data. Again, half of the models used all 20 variables while the others used only the five significant variables. LDA models provided correct classifications in 62.5% to 87.5% of cases. The classifications provided by all of the different models were compared with kappa statistics, yielding kappa values ranging from 0.25 to 1.0. We conclude that ANN models based on DNA methylation profiles can objectively classify SCLC and NSCLC cells lines with substantial to perfect concordance, while LDA models based on DNA methylation profiles provide poor to substantial concordance. Our work supports the promise of ANN analysis of DNA methylation data as a powerful approach for the development of automated methods for lung cancer classification.
J Mol Diagn 2004 Feb
PMID:Classification of individual lung cancer cell lines based on DNA methylation markers: use of linear discriminant analysis and artificial neural networks. 1473 24

Defects in the system controlling the cell cycle can lead an increased proliferation of cancer cells. The aim of our study was to analyze the relationship between genetic changes leading to inactivation of the CDKN2A gene and subsequent alteration of protein expression in squamous cell cancer of the larynx (SCCL) in connection with the clinical and histopathological course of the disease. Analysis was carried out on DNA isolated from the blood and primary larynx cancer cells of 62 patients. To investigate loss of heterozygosity (LOH), PCR fragment analysis was applied. The size and quantity of fluorescent PCR products were evaluated in an automated sequencer. Specific chemical methylation with sodium bisulfite in a sequential PCR reaction (MSP) was applied to analyze promoter methylation. Cancer tissue sections served to determine the level of protein expression with immunohistochemical (IHC) staining and commercial antibodies. LOH at the CDKN2A locus was observed in 55.35% of the informative cases. Aberrant methylation was found in 37.5% and a decreased level of protein expression observed in 45% of all informative cases. Whenever P16 expression was decreased, LOH and promoter hypermethylation at CDKN2A were observed with a frequency of 73.33% and 80.95%, respectively (Fisher's test, P<0.005). Sixty-nine percent of G3 tumors had at least one genetic alteration at CDKN2A, compared with 40.9% of G1 cancers. The results indicate that CDKN2A inactivation played a significant role in the development of squamous cell carcinoma of the larynx.
Mol Carcinog 2004 Mar
PMID:Inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene in squamous cell carcinoma of the larynx. 1499 44


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