Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p16INK4a and p15INK4b are cell cycle regulators that specifically bind to and inhibit the cyclin D-dependent kinases, cdk4 and cdk6. Because these genes undergo frequent deletions and/or mutations in various human cancers, we examined the status and expression of the cognate mouse cdk inhibitors in a panel of 29 cell lines, as well as in 12 primary tumors, representing different stages of mouse skin carcinogenesis. Deletion of p16INK4a and/or p15INK4b was seen in 8 of 10 cell lines derived from spindle carcinomas, the most advanced stage of skin carcinogenesis. Five showed deletion of both genes, and three had independent deletions of p16INK4a or p15INK4b, but in those retaining p16INK4a, expression of the protein was not detected. By contrast, none of 19 more differentiated squamous cell lines exhibited such deletions. In several cases, primary tumor DNA was available, and two spindle tumors showed the same deletion pattern as observed in the corresponding cell lines. In apparent contrast, comparison of two clonally related squamous and spindle cell lines derived from a single carcinoma showed unusually high levels of p16INK4a and p15INK4b only in the invasive spindle cells. Therefore, deletion or altered regulation of p16INK4a and p15INK4b occur concomitantly with the loss of differentiation associated with the late spindle stage of tumor progression in mouse skin.
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PMID:Deletion and altered regulation of p16INK4a and p15INK4b in undifferentiated mouse skin tumors. 758 67

We examined the genomic status of cyclin-dependent kinase-4 and -6 inhibitors, p16INK4,p15INK4B, and p18, in 40 primary lung cancers and 31 metastatic lung cancers. Alterations of the p16INK4 gene were detected in 6 (2 insertions and 4 homozygous deletions) of 22 metastatic non-small cell lung cancers (NSCLCs; 27%), but none were detected in 25 primary NSCLCs, 15 primary small cell lung cancers (SCLCs), or 9 metastatic SCLCs, indicating that mutation in the p16INK4 gene is a late event in NSCLC carcinogenesis. Although three intragenic mutations of the p15INK4B gene were detected in 25 primary NSCLCs (12%) and five homozygous deletions of the p15INK4B gene were detected in 22 NSCLCs (23%), no genetic alterations of the p15INK4B gene were found in primary and metastatic SCLCs. The p18 gene was wild type in these 71 lung cancers, except 1 metastatic NSCLC which showed loss of heterozygosity. We also examined alterations of these three genes and expression of p16INK4 in 21 human lung cancer cell lines. Alterations of the p16INK4 and p15INK4B genes were detected in 71% of the NSCLC cell lines (n = 14) and 50% of the NSCLC cell lines (n = 14), respectively, but there were none in the 7 SCLC cell lines studied. No p18 mutations were detected in these 21 cell lines. These results indicate that both p16INK4 and p15INK4B gene mutations are associated with tumor progression of a subset of NSCLC, but not of SCLC, and that p15INK4B mutations might also be an early event in the molecular pathogenesis of a subset of NSCLC.
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PMID:Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer. 788 51

The p15(INK4B), p16(INK4) and p18 genes are members of the gene family coding for inhibitors of cyclin-dependent kinases 4 and 6. p15(INK4B) and p16(INK4) are located at 9p21, a chromosomal region frequently deleted in many human neoplasms. To examine the role of these 3 genes in lung carcinogenesis, somatic mutations within the genes were analyzed by single-strand conformation polymorphism and DNA sequencing in 71 non-small-cell lung cancer (NSCLC) samples. Six somatic mutations in the p16(INK4) gene and 3 cases with a polymorphic allele were observed. Loss of heterozygosity in the p18 gene was found in 1 sample. We did not find any intragenic mutations in the p15(INK4B) or p18 genes. We conclude that p16(INK4) mutations play a role in the formation of some NSCLCs, whereas the involvement of p15(INK4B) and p18 is uncommon.
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PMID:Intragenic mutations of the p16(INK4), p15(INK4B) and p18 genes in primary non-small-cell lung cancers. 863 83

The p16 (MTS-1) gene, a candidate tumor suppressor gene, was examined by means of Southern blot, PCR-SSCP (polymerase chain reaction-single-strand conformation polymorphism) and nucleotide analyses in 5 cases of primary malignant lymphoma of the brain. By Southern blot analysis, the p16 gene was found to be deleted in at least 4 cases, homozygously (3 cases) or hemizygously (1 case). The p15 (MTS-2) gene, another candidate tumor suppressor gene located in the vicinity of the p16 gene, to which it shows structural and functional similarity, was also found to be deleted in 4 cases. Our frequent detection (80%) of p16 and p15 gene deletions might suggest that these deletions are closely related to carcinogenesis in primary malignant lymphoma of the brain. SSCP and nucleotide analyses revealed no mutations of the p16 gene in any of the cases.
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PMID:Primary malignant lymphoma of the brain: demonstration of frequent p16 and p15 gene deletions. 869 17

Cyclin-dependent kinase-4 inhibitor genes (INK4) regulate the cell cycle and are candidate tumor-suppressor genes. To determine if alterations in the coding regions of the p18 and p19 genes, which are novel members of the INK4 family and if they correlate with the development of human cancer, 100 human cancer cell lines were analyzed. Two other INK4 gene family members, p15INK4b/MTS2 and p16INK4/MTS1 genes were also analyzed. Homozygous deletions of the p15INK4b/MTS2 gene were detected in 29 cancer cell lines. Thirty-five homozygous deletions and 7 intragenic mutations of the pl6INK4/MTS1 gene were also detected in these cell lines. Neither homozygous deletions nor intragenic mutations of the p18 and p19 genes were found except in an ovarian cancer cell line, SKOV3, harboring a single base pair deletion in exon 1 of p19. In p16INK4/MTS1 expression analysis, 5 cell lines with both authentic and alternative spliced p16INK4/MTS1 mRNA had no detectable p16INK4/MTS1 protein. These results suggest the hypotheses that either post-translational modification or enhanced degradation may be responsible for the lack of detection of the p16INK4/MTS1 protein. Using Western blot analysis, subsets of 26 human cancer cell lines were examined for p18 expression and 39 cell lines for p19 expression. All of these cell lines expressed the p18 or p19 protein, with the exception of SKOV3, which did not express p19. Therefore, the INK4 gene family may be divided into 2 groups. One group includes p15INK4b/MTS2 and p16INK4/MTS1, in which genetic and epigenetic alterations might contribute to the development of human cancers. The other group includes p18 and p19, in which somatic mutations are uncommon in many types of human cancer, and their role in human carcinogenesis and cancer progression is uncertain.
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PMID:Molecular analysis of the cyclin-dependent kinase inhibitor genes p15INK4b/MTS2, p16INK4/MTS1, p18 and p19 in human cancer cell lines. 893 42

Recent allelotyping of chemical-induced lung tumors in hybrid mice has detected loss of heterozygosity on chromosome 4 in a region involving the interferon-alpha (IFN-alpha gene cluster that is syntenic to human chromosome 9p21-22, the location of the p16INK4a (p16) and p15INK4b (p15) tumor suppressor genes. The purpose of the current investigation was to characterize the expression of p16 and p15 in lung tumors and tumor-derived cell lines induced in A/J mice by exposure to the tobacco-specific nitrosamine, 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK). Expression of p16 and p15 was detected in all primary lung tumors; however, levels of expression of p16 differed by up to 15-fold between tumors. This is the first study to note a marked difference in the expression of the p16 gene in primary lung tumors. The apparent low levels of expression seen in approximately half of the tumors was not attributed to deletion, mutation or methylation of the p16 gene. Conversely, the high levels of p16 expression were not the result of effects on the retinoblastoma gene (Rb) or cyclin D1 proteins but most likely in response to a dysfunction elsewhere within this pathway. In contrast to the detection of p16 expression in primary tumors, this gene was deleted in all four cell lines. Three of four cell lines also showed loss of the p15 gene. Mapping of these homozygous deletions on chromosome 4 revealed that the p16 gene resides near the D4MIT77 marker, which is located approximately 12 cM proximal to the IFN-alpha gene cluster, thereby implicating the p16 gene as one of the targets within the allelic deletions detected previously in primary lung tumors from hybrid mice.
Carcinogenesis 1997 Jan
PMID:Deletion and differential expression of p16INK4a in mouse lung tumors. 905 97

In the present study, we analyzed human ovarian carcinoma cell lines for abnormalities in the tumor suppressor gene Rb (retinoblastoma) and in cyclin-dependent kinase 4 (CDK4) inhibitor genes (p16INK4 and p15INK4B) using molecular biology techniques. For the Rb gene, in all six cell lines (PA-1, Caov-3 and -4, OVCAR-3, SK-OV-3, and Kuramochi), Rb gene abnormality was not detected using Southern blotting. In the Caov-3 cell line transcripts were not detectable by either Northern blot or polymerase chain reaction. Sequence analysis of the entire coding region of the Rb gene revealed point mutations (AAC to GAC) resulting in codon 123 (Asn to Asp) changes in the Caov-4 cell line. In the PA-1 cell line both wild-type Rb and mutant-type Rb (codon 798: CGG to TGG) were expressed, and in the OVCAR-3 cell line both wild-type Rb and mutant-type Rb (codon 704: ATG to GTG) were expressed. In four of six human ovarian carcinoma cell lines Rb gene abnormality was detected. For the p16INK4 and p15INK4B genes, only the SK-OV-3 cell line had abnormalities. There was a gene rearrangement or minor deletion of the p16INK4 gene in the SK-OV-3 cell line, while the p15INK4B gene was deleted in this cell line. In the SK-OV-3 cell line no mRNAs of p16INK4 and p15INK4B were expressed. At the point of Rb gene inactivation, we can explain five cell lines of six: four cell lines had abnormalities in the Rb gene itself, which is another mechanism by which the Rb gene is inactivated, while one cell line (SK-OV-3) had abnormalities in CDK4 inhibitor genes, another of the inactivation mechanisms of the Rb gene. These data suggest that abnormalities of Rb and CDK4 inhibitor genes (p16INK4, p15INK4B) may be involved in human ovarian carcinogenesis.
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PMID:Analysis of the Rb gene and cyclin-dependent kinase 4 inhibitor genes (p16INK4 and p15INK4B) in human ovarian carcinoma cell lines. 919 86

Transgenic mice overexpressing the pim-1 oncogene in their lymphoid compartment display a low incidence of spontaneous T-cell lymphomas, but are highly susceptible to point mutation-inducing genotoxic carcinogens. We show here that total body X-irradiation, which causes mainly chromosomal deletions, rearrangements and amplifications, significantly enhances lymphoma development in E mu-pim-1 transgenic mice. The X-ray-induced E mu-pim-1 and non-transgenic lymphomas have a comparable high cell turnover as shown by a relatively high S-phase fraction and a high apoptotic activity. Consistent with previous observations, in 75% of all lymphomas c-myc mRNA levels are 5- to 20-fold higher than in control, non-lymphomatous spleen/thymus. The expression of other oncogenes, which have previously found to be activated in combination with pim-1 in lymphomagenesis, such as gfi-1/pal-1, frat-1 and tiam-1, and also of the mdm-2 and mdm-x oncogenes, appeared not to be affected. Deletions and/or rearrangements of the p16INK4A and p15INK4B tumor suppressor genes were seldom observed (in three out of 92 X-ray-induced lymphomas). Strikingly, in addition to the high mRNA levels of the pim-1 transgene, the levels of the endogenous pim-1 transcripts were elevated significantly in 16% of the X-ray-induced E mu-pim-1 lymphomas compared with control spleen, even surpassing the level of the pim-1 transgene mRNA by 3- to 5-fold. In combination with previous results, which showed that the lymphoma incidence increased concordantly with higher levels of pim-1, this supports the notion that pim-1 can contribute to lymphomagenesis in a dose-dependent manner.
Carcinogenesis 1998 May
PMID:X-ray-induced lymphomagenesis in E mu-pim-1 transgenic mice: an investigation of the co-operating molecular events. 963 73

Cyclin-dependent kinase (CDK) inhibitor genes have recently been proposed as new tumor suppressor genes. To define the possible participation of CDK inhibitor genes in lung carcinogenesis, we investigated the alterations of p15INK4B, p16INK4A, p21Waf1, and p27Kip1 genes in 34 human lung cancer cell lines using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), direct sequencing, and southern dot blot methods. Among the four CDK inhibitor genes, alterations of only the p16INK4A gene were found in 8 out of 34 (24%) cell lines, and all eight cell lines having a p16INK4A gene alteration had an alteration of either the K-ras of p53 gene. Conversely, p16INK4A gene alterations were found in none of the 3 cell lines having Rb gene alterations and none of the 3 cell lines having amplification of the N-myc gene. Polymorphism was found in both p21Waf1 and p27Kip1 genes, but no association was found between the polymorphism and alterations of other genes. These results suggest that p16INK4A gene alterations may play a certain role for lung carcinogenesis in co-operation with either K-ras or p53 gene alterations.
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PMID:Coincidental alterations of p16INK4A/CDKN2 and other genes in human lung cancer cell lines. 967 67

p16INK4a and p15INK4b genes, which encode two functionally related CDK inhibitors, recently emerged as candidate tumor suppressor genes since they were both localized to 9p21, which frequently undergoes hemizygous and homozygous deletion in a variety of tumor types. To determine the mode of inactivation of these two genes in human esophageal squamous cell carcinoma (ESCC), we performed multiple molecular analyses in 60 ESCC specimens from Linxian, China using DNA methylation assay, LOH analysis, deletion screening and SSCP-sequencing. We observed that p16INK4a inactivation was predominantly associated with aberrant methylation in the CpG island of its promoter region, whereas p15INK4b frequently had homozygous deletions. Compared with aberrant methylation, which occurred in 17 of 34 cases, homozygous deletion of p16INK4a and LOH at its nearby D9S942 microsatellite marker were observed at a much lower frequency (17%). Intragenic mutation in p16INK4a gene was rare. In contrast, homozygous deletion in p15INK4b and LOH at the nearby D9S171 marker were observed at frequencies of 35 and 47%, respectively, and the two events were significantly associated with each other. On the other hand, aberrant methylation of p15INK4b was relatively infrequent (6/34) and occurred concomitantly with p16INK4a methylation. Among the 60 cases, only four contained a continuous homozygous deletion spanning both p15INK4b and p16INK4a. Six cases were exclusively deleted at p16INK4a and 17 exclusively deleted at p15INK4b. LOH at D9S942 and D9S171 was also found to be mutually exclusive. Our results suggest that the alteration mode at 9p21 was not uniform, and the two genes were inactivated by distinct mechanisms. Altogether, 68% of the samples harbor at least one type of alteration in p16INK4a gene and 50% of the samples were altered in p15INK4b gene, indicating that they are the frequent inactivating targets during ESCC development.
Carcinogenesis 1999 Jan
PMID:Aberrant methylation of p16INK4a and deletion of p15INK4b are frequent events in human esophageal cancer in Linxian, China. 993 53


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