Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p16INK4A/MTS1 (p16) and p15INK4B/MTS2 (p15) genes map to 9p21 where genetic alterations have been frequently reported in various human tumors. Using the polymerase chain reaction (PCR), we investigated the loss of these genes on primary glioma samples and cultured glioma cells. All or any of three exons of the p16 gene were homozygously delted in 11 (35.5%) of 31 glioblastomas, none of 9 anaplastic astrocytomas and 5 astrocytomas, and in all 6 human glioma cell lines. Exon 2 of the p15 gene was homozygously deleted in 4 (12.9%) of 31 glioblastomas, but not in lower grade gliomas. It was homozygously deleted in 5 (83.3%) of 6 glioma cell lines. In 12 short-term cultures of cells derived from primary glioma samples, 5 (41.7%) and 2 (16.7%) glioblastoma-derived cells had homozygous deletion of all or any of the three exons of the p16 gene and exon 2 of the p15 gene, respectively. The deletion pattern of these genes in cultured cells was completely consistent with that seen in the primary tumors. Furthermore, two long-term cultures retained both genes that were identical to those in the original tumor tissues. Our results indicate that loss of the p16 and p15 genes may be involved in tumor progression in human gliomas, especially in the development of glioblastoma, that this loss may give growth advantage to the cells in culture, and that it is not the result of culture artifacts.
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PMID:Homozygous deletions of p16INK4A/MTS1 and p15INK4B/MTS2 genes in glioma cells and primary glioma tissues. 749 69

The P15 gene (MTS2) encodes a cyclin-dependent kinase (CDK) inhibitor with considerable sequence identity and biochemical similarity to the CDK inhibitor p16. It is closely linked to the P16 gene (MTS1) and is homozygously deleted in many tumor cell lines. These features suggest that p15 may be a tumor suppressor. We have determined the genomic structure of P15 and examined its pattern of mRNA expression. In addition, we have shown that ectopic expression of p15 inhibits growth of tumor-derived cell lines. We have also searched for P15 mutations in tumor cell lines and in 9p21-linked melanoma kindreds. Other than the previously described homozygous deletions, no mutations of P15 were found. Collectively, these observations suggest a role for p15 in growth regulation, but a limited role for p15 in tumor progression.
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PMID:Genomic structure, expression and mutational analysis of the P15 (MTS2) gene. 767 59

Several studies support a role for the multiple tumor suppressor gene (MTS1) in the malignant progression of different tumor types. In this study we have examined the status of the MTS1 gene in a variety of non-astrocytic tumors of the central nervous system. It was not possible, using multiplex PCR with primers for MTS1 and D9S196, a chromosome 9q marker, to demonstrate deletions of MTS1 in 59 primary non-astrocytic tumors. Two out of 5 (40%) secondary tumors showed evidence of homozygous deletion of MTS1. The results obtained here for primary non-astrocytic tumors contrast with those previously described for astrocytic tumors where a high frequency of deletions of MTS1 was associated with tumor progression.
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PMID:Homozygous deletions of the MTS1 gene are rare in non-astrocytic brain tumors. 779 50

Homozygous deletions of the tumor suppressor gene p16/MTS1 were reported in a wide variety of tumors and tumor cell lines. Its product inhibits the phosphorylation of the retinoblastoma protein (pRb) by CDK4 and CDK6. Because phosphorylation of pRb is a major regulatory event in the activation of the transcription factor E2F, a role for p16 in the regulation of E2F-dependent transcription was presumed. We investigated the effect of the loss of p16 on E2F-mediated transcription in a tumor progression model consisting of three cell lines originating from a common precursor cell--one p16-positive cell line established from the primary biopsy and two lines derived from more advanced stages of the tumor representing the same cell clone after loss of p16. We observed up- and deregulation of E2F-dependent transcription during the cell cycle of the p16-negative cell clones, which returned to normal after transient expression of p16. This p16-dependent regulation affects a set of enzymes necessary for the activation of all four DNA precursors; it is paralleled by the interconversion of transcriptionally active free E2F and transcriptionally inactive higher molecular complexes of E2F and is dependent on the existence of endogenous pRb. Furthermore, we show that p16-negative cell clones exhibit a growth advantage compared to their p16-positive counterparts. One might speculate that one feature of tumor progression could be deregulation of E2F-dependent transcription caused by loss of p16.
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PMID:Loss of the p16/MTS1 tumor suppressor gene causes E2F-mediated deregulation of essential enzymes of the DNA precursor metabolism. 856 96

Wild-type P16/CDKN2 (p16INK4A, MTS1) cDNA, directed by the cytomegalovirus (CMV) immediate early promoter, was transfected into RT4 and RT112 bladder-carcinoma cell lines bearing a mutated endogenous P16/CDKN2 gene and lacking endogenous P16/CDKN2 respectively. In both cases, only transfected clones with rearranged exogenous P16/CDKN2 cDNA could be grown and propagated in cell culture. This result is reminiscent of transfection of wild-type p53 into cells with a deleted or mutated endogenous gene and suggests that P16/CDKN2, over-expressed under control of the strong CMV promoter, induces growth arrest in RT4 and RT112 cells. Transfer of human chromosome 9 to RT4 cells produced RT4/H9 hybrid clones retaining the P16/CDKN2 gene, since in RT4/H9 cell clones P16/CDKN2-gene expression is modulated by the physiological control of chromosomal regulatory sequence. All the RT4/H9 clones lost the entire chromosome 9, except clone 4 and clone 5, which maintained a deleted and an intact chromosome 9 respectively. Loss of several loci in 9p21, including P16/CDKN2, in tumors induced in nude mice by clone 4 and clone 5 suggests that P16/CDKN2 or other genes in 9p21 suppress tumorigenicity in bladder-carcinoma cells. Tumors induced by clone 4 and clone 5 show loss of markers in 9q. The regions 9q22.3, 9q32-33 and 9q34.2, which were maintained in the 2 clones and lost in their derived tumors, may contain tumor-suppressor genes relevant in bladder carcinoma. The results of this study suggest that the P16/CDKN2 gene controls growth of bladder-carcinoma cells when it is over-expressed, and may be involved in the development of bladder carcinoma, but other genes in 9p21 and 9q may participate in bladder-cancer progression.
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PMID:Growth arrest and suppression of tumorigenicity of bladder-carcinoma cell lines induced by the P16/CDKN2 (p16INK4A, MTS1) gene and other loci on human chromosome 9. 863 1

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

The p16 (CDKN2,MTS1) gene is located at 9p21 and its product, p16, inhibits the cyclin D/CDK4 complex. Loss of heterozygosity on chromosome 9p is very common in human bladder carcinomas and has been found in all stages of lesions, suggesting that it occurs early in bladder tumor progression. Several studies have revealed frequent homozygous deletion of the p16 gene in cell lines, and that such deletions are also common in some types of cancers. In addition, point mutations in the p16 gene have been identified in several types of neoplasia. In the present examination of urinary bladder tumors, no p16 gene mutations were detected, but nine cases out of 23 (39%) showed decreased mRNA expression, revealed by the reverse transcriptase polymerase chain reaction. There were no histological differences apparent between those cases with normal and those with decreased p16 expression. These results indicate that while p16 gene mutations may be rare, changes in the level of the p16 transcripts could play a role in human bladder carcinoma development.
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PMID:Decreased expression of the p16/MTS1 gene without mutation is frequent in human urinary bladder carcinomas. 907 Mar 36

Inactivation of relevant tumor-suppressor genes by allelic or homozygous deletion is a characteristic event in tumor cells. Here, the prognostic value of allelic deletions on 5p13-12 at the putative del-27 tumor-suppressor locus and in the APC tumor-suppressor gene on 5q21, as well as homozygous deletions of the MTS1 (p16INK4, CDKN 2) tumor-suppressor gene on 9p21 was assessed in 87 bladder cancers using microdissection and PCR-based assays. Tumor-specific LOH was detected in 10 of 38 (26%, del-27), and 15 of 30 (50%, APC) informative specimens. Homozygous deletion of the MTS1 gene was detected in 33% of 84 tumors investigated. These deletion frequencies implicate the 3 tumor-suppressor regions in the genesis of transitional-cell carcinoma. In contrast to deletions of the APC or MTS1 genes, LOH at the del-27 locus correlated with tumor progression. This suggests that loss of the putative tumor-suppressor gene DEL-27 is involved in an aggressive behavior of the tumor cells and appears to be a prognostic marker for the clinical outcome of patients with transitional-cell carcinoma.
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PMID:Deletion analysis at the DEL-27, APC and MTS1 loci in bladder cancer: LOH at the DEL-27 locus on 5p13-12 is a prognostic marker of tumor progression. 922 7

The product of the MTS1/CDKN2 gene (p16) and the retinoblastoma protein (pRB) inhibit cell cycle progression at the late G1 checkpoint. The absence of functional p16 or pRB has been identified in a variety of human tumors but has not been well studied in mesenchymal neoplasia. Using an immunohistochemical approach, the authors identified abnormal expression of either p16 or RB in 16 and 14 of 59 sarcomas, respectively, for an overall abnormality rate of 51%. Specific rates of abnormality varied by histological subtype, with leiomyosarcomas most commonly affected by loss of either tumor-suppressor gene product. There was no significant correlation between p16 or RB expression and overall grade, mitotic grade, or tumor progression for sarcomas. In contrast, no fibromatoses and other spindle cell neoplasms of low malignant potential displayed abnormal p16 expression, and only 4 of 23 cases showed loss of pRB expression. These data show that aberrant expression of p16/pRB is one of the most common molecular derangements in sarcomagenesis.
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PMID:Loss of RB and MTS1/CDKN2 (p16) expression in human sarcomas. 926 24

The familial melanoma gene (INK4a/MTS1/CDKN2) encodes potent tumor suppressor activity. Although mice null for the ink4a homolog develop a cancer-prone condition, a pathogenetic link to melanoma susceptibility has yet to be established. Here we report that mice with melanocyte-specific expression of activated H-rasG12V on an ink4a-deficient background develop spontaneous cutaneous melanomas after a short latency and with high penetrance. Consistent loss of the wild-type ink4a allele was observed in tumors arising in ink4a heterozygous transgenic mice. No homozygous deletion of the neighboring ink4b gene was detected. Moreover, as in human melanomas, the p53 gene remained in a wild-type configuration with no observed mutation or allelic loss. These results show that loss of ink4a and activation of Ras can cooperate to accelerate the development of melanoma and provide the first in vivo experimental evidence for a causal relationship between ink4a deficiency and the pathogenesis of melanoma. In addition, this mouse model affords a system in which to identify and analyze pathways involved in tumor progression against the backdrop of genetic alterations encountered in human melanomas.
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PMID:Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. 935 52


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