Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In human cervical carcinomas papillomavirus DNA is frequently integrated in the cell genome. We have cloned the integration site of human papillomavirus-18 DNA in human chromosome region 12q13-15 present in the SW756 cervical carcinoma cell line. Viral DNA is broken from nucleotides 2643 to 3418 in the E1 and E2 open reading frames, resulting in a deletion of 775 bases of viral DNA. Cloning and sequence analysis of the rearranged and germline alleles shows that there is no homology between the target cellular and viral DNA, suggesting it is a nonhomologous recombination. The target cellular region is called papillomavirus associated locus 2 (PAL2). The 5'- and 3'-flanking probes derived from the hybrid viral-cellular clone detect completely different germline restriction fragments in DNA from cells with normal chromosome 12. There is no overlap between the restriction maps of the target germline clones obtained with 5'- and 3'-flanking probes. Probes from these germline clones beyond the breakpoint position do not detect any DNA rearrangement in SW756 cells DNA. These data prove that there is a deletion of cellular DNA as consequence of the integration, with an estimated minimum size of 14 kilobases. Both cellular flanking probes are outside the amplicon of this chromosome region identified in the OSA and RMS13 sarcoma cell lines, comprising SAS-CHOP-CDK4-MDM2 genes and where translocation breakpoints are located in liposarcomas. The integration at 12q13-15 might have been selected by its contribution to the tumor phenotype.
 ...
PMID:Deletion in human chromosome region 12q13-15 by integration of human papillomavirus DNA in a cervical carcinoma cell line. 759 43

Homozygous deletions of the putative tumour-suppressor gene CDKN2, which encodes an inhibitor of cdk4, have been detected in a high percentage of cancer cell lines of various histological types. In the present study, 109 human sarcomas were examined for homozygous deletions and for mRNA expression levels of the CDKN2 gene. Altogether, deletions were found in only eight (7%) of the cases, but, interestingly, in two (of eight) malignant Schwannomas and in two (of five) rhabdomyosarcomas. In comparison, such deletions were seen in only one (of 21) osteosarcomas and in none of 20 MFHs and 21 liposarcomas. Notably, highly elevated CDKN2 mRNA levels were found in 33% of the sarcomas, whereas no detectable transcript was present in 12 normal tissues. Amplifications of CDK4 and CCND1 (cyclin D1) were observed in 11% and 4% of the sarcomas respectively, but never in tumours with CDKN2 deletions. The level of CDK4 mRNA expression was increased in nine tumours in addition to the 12 samples with CDK4 amplification. Increased levels of the cyclin D1 transcript was found in 37 cases, four with and 33 without amplification. The data indicate that aberrations of these functionally related genes, or in regulation of the expression of the kinase, the activator or the inhibitor, may participate in sarcoma development. Furthermore, the data suggest that homozygous CDKN2 deletions may be of dissimilar significance in different sarcoma subtypes.
 ...
PMID:Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas--relationship to amplification and mRNA levels of CDK4 and CCND1. 764 Feb 24

The 34-kilodalton cyclin-dependent kinase, p34cdk4, is a major catalytic subunit of mammalian D-type cyclins, which act during the G1 phase of the cell cycle to enforce the decision of cells to enter S phase. A murine complementary DNA clone was used to clone the cognate human CDK4 gene, which was localized to human chromosome 12, band q13, by fluorescence in situ hybridization. Because this chromosomal band contains the GLI and MDM2 genes, which are frequently amplified in human sarcomas, we analyzed CDK4 copy number and expression in a panel of sarcoma cell lines. An osteosarcoma cell line, OsACL, manifested a 25-fold increased copy number of CDK4, amplified concordantly with both GLI and MDM2, whereas a rhabdomyosarcoma cell line, SJRH30, was found to have an amplicon that included CDK4 and GLI but not MDM2. CDK4 mRNA and protein were overexpressed in both cell lines, and nucleotide sequencing analysis indicated that the gene had not sustained mutations. These observations provide the first evidence for amplification of a gene encoding a cell division cycle protein kinase, complement recent data indicating that genes encoding D-type cyclins are targets of chromosomal rearrangement and gene amplification in tumor cells, and suggest that CDK4 amplification might contribute to oncogenesis.
 ...
PMID:Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. 822 95

Amplification and overexpression of genes involved in cellular growth control occur frequently in human tumors. Using a chromosome microdissection-based hybrid-selection strategy, we recently identified two novel genes (OS-9 and OS-4) within 12q13-15, a region frequently amplified in human cancers. We now report further characterization of the full-length OS-9 cDNA sequence consists of 2785 bp from which an open reading frame (ORF) with 667 amino-acid residues was deduced, The predicted polypeptide was water soluble and acidic. We also demonstrate that the OS-9 gene encoded a 2.8-kb mRNA transcribed in all 16 human tissues examined, suggesting that OS-9 is ubiquitously expressed in human tissues. OS-9 was co-amplified with CDK4 in three of five sarcoma tissues. Homology analysis of the amino-acid sequence reveals significant similarities between OS-9 and two ORFs deduced from genomic sequences in Caenorhabditis elegans and Saccharomyces cerevisiae. The region of similarity extended over 200 residues (approximately one-third of each ORF), and eight cysteines were conserved in all three ORFs. These observations suggest that this region comprises a functional domain present in a novel evolutionarily conserved gene family defined by OS-9.
 ...
PMID:Complete sequence analysis of a gene (OS-9) ubiquitously expressed in human tissues and amplified in sarcomas. 863 85

Amplification of MDM2 and CDK4 is observed frequently in human sarcomas. Although overexpression of these protooncogenes might inhibit growth regulation through the TP53- and retinoblastoma tumor suppressor protein (RB)-mediated pathways, neither gene was included consistently in all of the amplicons observed in our sarcoma panel. It was unclear whether both of these genes were selected for during amplification. Furthermore, in some samples without amplification of MDM2 or CDK4, comparative genomic hybridization showed amplification in the 12q13-15 region, suggesting that another selection mechanism might also be involved. To investigate the possibility that another target gene, which may be located between CDK4 and MDM2, could be the driving force, we characterized the involvement of 17 loci from this region in 12q13-15 amplicons that were detected previously in 21 sarcoma samples. The results showed discrete amplicons around MDM2 and CDK4 with reduced amplification of the intervening sequences. This suggests that there is separate selection for amplification of the two genes, and it makes the possibility of a common selective gene unlikely. Furthermore, D12S8, localized distal to MDM2, was amplified almost as frequently as MDM2 and was also amplified in one of the samples without MDM2 or CDK4 amplification. The data suggest that amplification of at least three different regions within the 12q13-15 segment may be selected for in tumor cells involving MDM2, CDK4, or a more distally located gene, possibly near D12S8.
 ...
PMID:Separate amplified regions encompassing CDK4 and MDM2 in human sarcomas. 894 7

Cytogenetic and molecular genetic studies were performed on a pleomorphic sarcoma removed from the left atrium of a 15-year-old girl. Histologic analysis was consistent with a storiform-pleomorphic malignant fibrous histiocytoma (MFH). Although MFH is the most common soft-tissue sarcoma of late adulthood. It is extremely rare in childhood and its existence in the pediatric population remains controversial. Cytogenetic analysis revealed several alterations previously associated with adult MFH, including abnormalities of chromosomal bands 11p11 and 19p13. Moreover, the tumor demonstrated homogeneously staining regions (HSR) and double minute chromosomes (dmin) suggestive of gene amplification. We therefore screened the case for amplification of genes localized to chromosomal bands 12q13-14, including the putative protooncogenes MDM2, CDK4, SAS, CHOP, and CLI, which are frequently amplified and overexpressed in adult MFH. Southern and Northern blot analysis confirmed the coamplification of MDM2, CDK4, SAS, and CHOP. To our knowledge, such coamplification studies of the 12q13-14 amplicon have not been previously detected in pediatric MFH. Our results provide cytogenetic and molecular genetic evidence that pediatric and adult MFH are histogenetically related entities.
 ...
PMID:Cytogenetic and molecular genetic analysis of a pediatric pleomorphic sarcoma reveals similarities to adult malignant fibrous histiocytoma. 916 31

OS-9 gene is frequently coamplified with CDK4 gene in human sarcomas. We isolated and characterized three isoforms of OS-9 cDNA found in a myeloid leukemia HL-60 cDNA library. Isoform 1 consisted of 2,700 bp, from which a 667 amino acid sequence was deduced and found to be identical with that of OS-9 cDNA from osteosarcoma cells [Su et al. (1996) Mol. Carcinogen. 15, 270-275]. Isoform 2 cDNA lacked a 165 nucleotide sequence in the coding region. Isoform 3 cDNA had an additional 45 bp deletion in the coding region. Isoforms 2 and 3 encode 612 and 597 amino acid polypeptides, respectively. Comparison of their cDNA sequences with the genomic structure indicated that three isoforms are splice variants. Reverse transcription-polymerase chain reaction analysis showed predominant expression of isoform 2 mRNA in myeloid leukemia HL-60 cells, osteosarcoma OsA-CL cells and rhabdomyosarcoma Rh30 cells. Northern blotting revealed similar levels of expression of OS-9 gene in various tumor cell lines of sarcoma cells, carcinoma cells and myeloid leukemia cells, but 3-4 times higher expression in OsA-CL cells and Rh30 cells containing a homogeneously staining region of 12q13-15. OS-9 expression decreased in differentiation-induced HL-60 cells. Possible involvement of the OS-9 gene in cell growth is discussed.
 ...
PMID:Cloning and characterization of three isoforms of OS-9 cDNA and expression of the OS-9 gene in various human tumor cell lines. 956 20

The pl6INK4a/MTS1 (p16) gene encodes a specific inhibitor of cyclin-dependent kinase (CDK)4 and CDK6. The p16 gene is frequently mutated or deleted in many types of cancer cell lines as well as in certain types of primary tumors. p16 knockout mice are viable but predisposed to sarcoma and B-cell lymphoma. To investigate the role of p16 in human soft-tissue sarcoma tumor progression, we examined the p16 gene by Southern blot analysis and PCR sequencing in 30 pairs of primary soft-tissue sarcomas and autologous normal tissue. Only one tumor sample showed possible rearrangement of the p16 gene. In contrast, Western blot analysis of the p16 protein in 20 pairs of samples showed decreased p16 expression in only 20% of the tumors but elevated p16 expression in 40% of the tumors when compared with the autologous normal controls. Overexpression of p16 was not concomitant with loss of the RB protein as is found in several other types of cancers, because more than one-half of the tumors with increased p16 expression also had high levels of RB protein. On the other hand, the p16 target protein CDK4 was overexpressed in at least 60% of the tumors. In the majority of cases, CDK4 overexpression accompanied elevated p16 and/or RB levels. Our results suggest that: (a) alteration of the p16 gene is infrequent in primary soft-tissue sarcoma; (b) Cdk4 may act as an oncogene in soft-tissue sarcoma; and (c) elevated p16 and RB levels might be the result of compensatory up-regulation of these proteins to counteract CDK4 overexpression in these tumors. Our results also suggest that it is more informative to examine aberrations in the "p16-CDK4/cyclin D-RB" pathway than to selectively examine individual components in this pathway when investigating genetic changes involved in human malignancy.
 ...
PMID:Infrequent mutation of the p16/MTS1 gene and overexpression of cyclin-dependent kinase 4 in human primary soft-tissue sarcoma. 956 3

The p16INK4A/CDKN2/MTS1 gene encodes a specific inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. This study investigates p16INK4A gene status and expression in mesenchymal tumours, in particular soft tissue sarcomas (STSs). Employing non-radioactive polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) sequencing, no p16INK4A mutation was found in 86 samples taken from 74 mesodermal tumours with known p53 gene status. This suggests that p16INK4A gene alterations, inc contrast to p53, are not involved in the progression of STS. This finding is supported by the reports of a low frequency of deletions and intragenic mutations in STS. Furthermore, by immunohistochemistry (IHC), an inverse correlation was established between p16INK4A and RB positivity for 62 per cent of the frozen tumour samples investigated. However, alterations in other components of the pRh/p16INK4A/ CDK4/cyclin D1/E2F pathway have been proven crucial for tumourigenesis in human sarcomas.
 ...
PMID:No p16INK4A/CDKN2/MTS1 mutations independent of p53 status in soft tissue sarcomas. 958 21

Several forms of human sarcoma, lymphoma, and leukemia are characterized by somatically acquired chromosome translocations that result in fusion genes that encode chimeric transcription factors with oncogenic properties. We have used cDNA microarrays containing 1238 cDNAs to investigate the gene expression profile of a group of seven alveolar rhabdomyosarcoma (ARMS) cell lines characterized by the presence of the PAX3-FKHR fusion gene. Using the method of multidimensional scaling to represent the relationships among the cell lines in two-dimensional Euclidean space, we determined that ARMS cells show a consistent pattern of gene expression, which allows the cells to be clustered together. By searching across the seven ARMS cell lines, we found that 37 of 1238 genes were most consistently expressed in ARMS relative to a reference cell line. Only three of these genes have been previously reported to be expressed in ARMS. Among these 37 were genes related to both primary (PAX3-FKHR) and secondary (CDK4) genetic alterations in ARMS. These results in ARMS demonstrate the potential of cDNA microarray technology to elucidate tumor-specific gene expression profiles in human cancers.
 ...
PMID:Gene expression profiling of alveolar rhabdomyosarcoma with cDNA microarrays. 982 99


1 2 3 4 5 6 7 8 9 10 Next >>