Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of cyclin-dependent kinases (CDKs) by interaction with cyclins regulates progression through cell cycle checkpoints. This process is counterbalanced by CDK inhibitors (CDKIs), which can inhibit progression through the cell cycle. Because CDKI expression acts to inhibit cellular proliferation, CDKIs may have a role as tumor suppressors. One class of CDKIs, characterized by the presence of ankyrin repeats, has at least four members (p15INK4B), p16INK4, p18, and p19). Two of these, p15INK4B, p16INK4, have been mapped to chromosome 9p21, a region of frequent loss in a wide variety of cancers. Alterations of p16INK4 have been detected in various tumors and cell lines. We analyzed p15INK4B, p16INK4, and p18 alterations in 52 osteosarcomas (including 11 explants), and 23 other various sarcomas. Single-stranded conformation polymorphism analysis [polymerase chain reaction (PCR-SSCP)] of the coding regions of these CDKI genes detected a missense mutation of p16INK4 exon 1 in one soft tissue sarcoma. Southern blotting detected complete deletion of p15INK4B and p16INK4 genes in osteosarcomas from 2 patients and a soft tissue sarcoma from another individual. Loss of heterozygosity (LOH) at chromosome 9p21 was observed with a microsatellite probe closely linked to the INK4 genes in the latter case. Deletions of both p15INK4B and p16INK4 genes were detected in five of eight osteosarcoma cell lines. By contrast, no alterations of p18 were detected in any sample. Together these data suggest that alterations of the p15INK4B and p16INK4 genes, but not p18, may occur in approximately 5% of sarcomas. However, deletions of the p15INK4B and P16INK4 genes are frequent in osteosarcoma cell lines and probably have a role in tumor cell growth in culture. Notably, all seven detectable deletions involved both p15INK4B and p16INK4 genes, suggesting that both contribute individual tumor suppressor activity.
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PMID:Alterations of the p15, p16,and p18 genes in osteosarcoma. 860 40

Inhibition of cyclin dependent kinases (CDK) by cyclin dependent kinase inhibitors (CDKI) blocks cell cycle progression and inhibits cellular proliferation. The archetypical member of the INK4 CDKI family, p16INK4A (also called CDKN2), is a tumor suppressor frequently deleted or mutated in certain neoplasms and many cell lines. Because p19INK4D has strong structural and functional similarity to p16INK4A, we have assessed its role as a tumor suppressor. This was accomplished by screening the p19INK4D coding region for mutations, deletions and rearrangements in sarcomas and non-small cell lung cancers. Alterations of the p19INK4D gene were found in samples from five of 67 (7%) patients with osteosarcomas and none were found in other types of sarcomas or in lung cancers. Five osteosarcoma samples had Southern blot patterns consistent with gene rearrangement. These samples included a primary and recurrent osteosarcoma from the same patient; both with the same rearrangement. Four samples had SSCP patterns consistent with sequence alterations, sequencing determined that three were due to silent base changes and apparently polymorphisms. Sequencing the fourth shifted band revealed a one base insertion causing a frameshift beginning with codon 27. In summary, these studies found alterations affecting the p19INK4D gene in a small but significant number of osteosarcomas. Presumably, abnormalities of this gene contribute to the development of cancer of bone cells.
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PMID:The p19INK4D cyclin dependent kinase inhibitor gene is altered in osteosarcoma. 924 58

Recent data suggest that deletion of p16INK4 and mutation of TP53 are among the most common genetic events in the development of human cancer, since the codified proteins act as brakes of the abnormal cell cycle. As the molecular events leading to the development of pediatric bone sarcomas remain unclear, we analyzed 75 osteosarcoma and Ewing sarcoma samples from 43 pediatric patients to search for alterations at the TP53 or p16INK4 tumor suppressor genes. By means of PCR-DGGE (polymerase chain reaction and denaturing gradient gel electrophoresis) we detected TP53 point mutations in 18.6% of the tumor samples, but no constitutional mutations. In the analysis of p16INK4, 7% of the samples harbored deletions of the gene but no point mutations were detected by SSCP (single strand conformation polymorphism) analysis, just the polymorphism Ala-->Thr at codon 148. These data support the hypothesis that TP53 alterations may play a role in the development of pediatric bone tumors and that the primary mechanism of inactivation of p16INK4 seems to be homozygous deletion rather than point mutation.
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PMID:Analysis of the p16INK4 and TP53 tumor suppressor genes in bone sarcoma pediatric patients. 930 18

The tumor suppressor p16(INK4a) inhibits cyclin-dependent kinases 4 and 6. This activates the retinoblastoma protein (pRB) and, through incompletely understood events, arrests the cell division cycle. To permit biochemical analysis of the arrest, we generated U2-OS osteogenic sarcoma cell clones in which p16 transcription could be induced. In these clones, binding of p16 to cdk4 and cdk6 abrogated binding of cyclin D1, p27(KIP1), and p21(WAF1/CIP1). Concomitantly, the total cellular level of p21 increased severalfold via a posttranscriptional mechanism. Most cyclin E-cdk2 complexes associated with p21 and became inactive, expression of cyclin A was curtailed, and DNA synthesis was strongly inhibited. Induction of p21 alone, in a sibling clone, to the level observed during p16 induction substantially reproduced these effects. Overexpression of either cyclin E or A prevented p16 from mediating arrest. We then extended these studies to HCT 116 colorectal carcinoma cells and a p21-null clone derived by homologous recombination. In the parental cells, p16 expression also augmented total cellular and cdk2-bound p21. Moreover, p16 strongly inhibited DNA synthesis in the parental cells but not in the p21-null derivative. These findings indicate that p21-mediated inhibition of cdk2 contributes to the cell cycle arrest imposed by p16 and is a potential point of cooperation between the p16/pRB and p14(ARF)/p53 tumor suppressor pathways.
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PMID:Induction of p21(WAF1/CIP1) and inhibition of Cdk2 mediated by the tumor suppressor p16(INK4a). 1020 15

Inheritance of a mutant allele of the breast cancer susceptibility gene BRCA1 confers increased risk of developing breast and ovarian cancers. Likewise, inheritance of a mutant allele of the retinoblastoma susceptibility gene (RB1) results in the development of retinoblastoma and/or osteosarcoma, and both alleles are often mutated or inactivated in sporadic forms of these and other cancers. We now demonstrate that the product of the RB1 gene, Rb, regulates the expression of the murine Brca1 and human BRCA1 genes through its ability to modulate E2F transcriptional activity. The Brca1 gene is identified as an in vivo target of E2F1 in a transgenic mouse model. The Brca1 promoter contains E2F DNA-binding sites that mediate transcriptional activation by E2F1 and repression by Rb. Moreover, ectopic expression of cyclin D1 and Cdk4 can stimulate the Brca1 promoter in an E2F-dependent manner, and this is inhibited by coexpression of the p16(INK4a) cyclin-dependent kinase inhibitor. The human BRCA1 promoter also contains a conserved E2F site and is similarly regulated by E2F1 and Rb. This functional link between the BRCA1 and Rb tumor suppressors may provide insight into the mechanism by which BRCA1 inactivation contributes to cancer development.
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PMID:Regulation of BRCA1 expression by the Rb-E2F pathway. 1066 Jun 29

We examined alterations of the p16INK4, p14ARF, p15, TP53, and MDM2 genes in 30 osteosarcomas and 24 Ewing sarcomas. Among 21 osteosarcomas and 24 Ewing sarcomas, p16INK4, p14ARF, and p15 abnormalities were found in 4 (19%), 2 (9%), and 3 (14%) osteosarcomas, respectively, and in 4 (17%), 3 (13%), and 4 (17%) Ewing sarcomas, respectively. The alterations of p16INK4, p14ARF, and p15 included homozygous deletions spanning all 3 genes, methylation of p16INK4 or p15, and a nonsense mutation of p16INK4, which simultaneously caused a missense mutation of p14ARF. Alterations of TP53 were found in 15 (50%) of 30 osteosarcomas and 1 (3%) of 24 Ewing sarcomas. None of the sarcomas showed MDM2 amplification. While TP53 abnormalities were far more frequent in osteosarcoma than in Ewing sarcoma, alterations of p16INK4, p14ARF, and p15 were present at similar frequencies in the two types of sarcoma. The event-free survival (EFS) was worse in Ewing sarcoma patients with p16INK4 and p14ARF mutation/deletion than in those without the mutation/deletion (P = 0.019), and EFS was worse in osteosarcoma patients with TP53 alterations than in those without TP53 alterations (P = 0.048). The different incidence of TP53 abnormalities in the 2 types of sarcoma may reflect differences of the molecular processes through which the 2 types of tumor develop.
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PMID:Analysis of the p16INK4, p14ARF, p15, TP53, and MDM2 genes and their prognostic implications in osteosarcoma and Ewing sarcoma. 1094 97

The activity of the retinoblastoma protein pRB is regulated by phosphorylation that is mediated by G(1) cyclin-associated cyclin-dependent kinases (CDKs). Since the pRB-related pocket proteins p107 and p130 share general structures and biological functions with pRB, their activity is also considered to be regulated by phosphorylation. In this work, we generated phosphorylation-resistant p107 and p130 molecules by replacing potential cyclin-CDK phosphorylation sites with non-phosphorylatable alanine residues. These phosphorylation-resistant mutants retained the ability to bind E2F and cyclin. Upon introduction into p16(INK4a)-deficient U2-OS osteosarcoma cells, in which cyclin D-CDK4/6 is dysregulated, the phosphorylation-resistant mutants, but not wild-type p107 or p130, were capable of inhibiting cell proliferation. Furthermore, when ectopically expressed in pRB-deficient SAOS-2 osteosarcoma cells, the wild-type as well as the phosphorylation-resistant pRB family proteins were capable of inducing large flat cells. The flat cell-inducing activity of the wild-type proteins, but not that of the phosphorylation-resistant mutants, was abolished by coexpressing cyclin E. Our results indicate that the elevated cyclin D- or cyclin E-associated kinase leads to systemic inactivation of the pRB family proteins and suggest that dysregulation of the pRB kinase provokes an aberrant cell cycle in a broader range of cell types than those induced by genetic inactivation of the RB gene.
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PMID:Collective inhibition of pRB family proteins by phosphorylation in cells with p16INK4a loss or cyclin E overexpression. 1115 55

Two different proteins, p16(INK4a) and p14(ARF), encoded by the INK4a/ARF locus play important roles in the RB and p53 pathways, respectively. This study was performed to determine genetic and epigenetic alterations in the INK4a/ARF locus and their effects on the growth of osteosarcoma. Among six cell lines examined, both p16(INK4a) and p14(ARF) exons were homozygously deleted in two cell lines, MG63 and HOS, and both p16(INK4a) and p14(ARF) promoters were methylated in one cell line, U2OS. Wild-type mRNA and proteins for p16(INK4a) and p14(ARF) were expressed in three other cell lines, SaOS2, HuO9, and G292. Transfection studies were performed using two cell lines, U2OS and MG63. Both the RB and p53 genes were wild types in U2OS, whereas p53 but not RB was mutated in MG63. Both p16(INK4a) and p14(ARF) suppressed the growth of U2OS, whereas p16(INK4a) but not p14(ARF) suppressed the growth of MG63. p53 only did not suppress the growth of MG63 either; however, coexpression of p14(ARF) with p53 increased the fraction of the G0/G1 phase in MG63 cells. The data presented here demonstrate the importance of genetic and epigenetic alterations in the INK4a/ARF locus for the growth of osteosarcoma and thus will be useful to further understand the biologic behavior of osteosarcoma in association with the defects in the p53 and RB pathways.
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PMID:Alterations in the INK4a/ARF locus and their effects on the growth of human osteosarcoma cell lines. 1194 35

Loss of p16(INK4a) protein expression has frequently been related to DNA methylation in association with gene silencing. Although the methylation status of exon1alpha for p16(INK4a) involvement in various cancers has been extensively analyzed, it has been pointed out that some inconsistencies existed in its relationship to gene silencing of p16(INK4a). In this study, we focused on the expression and methylation status in the regions of nt -478 to -201, containing a putative TATA box (nt -401 to -396), and nt -233 to 26, both in a recently cloned 5' upstream region of rat p16(INK4a). We showed that rat lung adenocarcinoma RLCNR did not express the p16(INK4a) gene, whereas rat osteosarcoma COS1NR and malignant fibrous histiocytoma MFH1NR both expressed it at levels similar to normal fibroblasts, even though the region of nt -233 to 26 was hypermethylated in COS1NR rather than RLCNR. In contrast, the CpG islands near the putative TATA box region were consistently methylated in RLCNR, but not in COS1NR and MFH1NR, as well as in normal fibroblasts. Treatment with 5-aza 2'-deoxycytidine induced expression of p16(INK4a) gene in RLCNR after 48 h, but no changes were observed in COS1NR and MFH1NR. The results indicated that methylation of CpG islands near a TATA box region played a critical role for gene silencing of the rat p16(INK4a) gene, rather than that of other regions.
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PMID:Expression of the p16INK4a gene and methylation pattern of CpG sites in the promoter region in rat tumor cell lines. 1469 43

p16(INK4a) (hereafter referred to as p16), a major cyclin-dependent kinase (CDK) inhibitor, is the product of a tumor-suppressor gene that has been found inactivated in different cancer types. In the present study, we sought to investigate the role of p16 in apoptosis induced by ultraviolet light (the most important etiological cause of skin cancer) and cisplatin (an anticancer DNA damaging agent). It is clearly shown that p16-compromised osteosarcoma U2OS cell line and p16-/- mouse embryo fibroblasts are sensitive to UV-induced apoptosis, as compared to their respective isogenic p16-expressing cells (EH1, EH2) and p16 +/+, indicating that p16 protects cells from undergoing apoptosis in response to UV light. Importantly, this reduction in UV-mediated apoptosis was associated with downregulation of the proapoptotic Bax protein, with no effect on Bcl-2 expression, suggesting that this antiapoptotic role of p16 is mediated via the intrinsic-mitochondrial pathway. On the other hand, p16 sensitized cells to cisplatin-mediated apoptosis through Bcl-2 decline. Interestingly, only proliferating but not G1-arrested EH1 cells underwent apoptosis in response to the anticancer drug. These novel findings provide further insight into the role of p16 in carcinogenesis, and has potential implications for future therapy strategies.
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PMID:The tumor suppressor p16(INK4a) gene is a regulator of apoptosis induced by ultraviolet light and cisplatin. 1471 25


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