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)

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.
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PMID:Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. 822 95

Glucocorticoids inhibit proliferation of many cell types, but the events leading from the activated glucocorticoid receptor (GR) to growth arrest are not understood. Ectopic expression and activation of GR in human osteosarcoma cell lines U2OS and SAOS2, which lack endogenous receptors, result in a G1 cell cycle arrest. GR activation in U2OS cells represses expression of the cyclin-dependent kinases (CDKs) CDK4 and CDK6 as well as their regulatory partner, cyclin D3, leading to hypophosphorylation of the retinoblastoma protein (Rb). We also demonstrate a ligand-dependent reduction in the expression of E2F-1 and c-Myc, transcription factors involved in the G1-to-S-phase transition. Mitogen-activated protein kinase, CDK2, cyclin E, and the CDK inhibitors (CDIs) p27 and p21 are unaffected by receptor activation in U2OS cells. The receptor's N-terminal transcriptional activation domain is not required for growth arrest in U2OS cells. In Rb-deficient SAOS2 cells, however, the expression of p27 and p21 is induced upon receptor activation. Remarkably, in SAOS2 cells that express a GR deletion derivative lacking the N-terminal transcriptional activation domain, induction of CDI expression is abolished and the cells fail to undergo ligand-dependent cell cycle arrest. Similarly, murine S49 lymphoma cells, which, like SAOS2 cells, lack Rb, require the N-terminal activation domain for growth arrest and induce CDI expression upon GR activation. These cell-type-specific differences in receptor domains and cellular targets linking GR activation to cell cycle machinery suggest two distinct regulatory mechanisms of GR-mediated cell cycle arrest: one involving transcriptional repression of G1 cyclins and CDKs and the other involving enhanced transcription of CDIs by the activated receptor.
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PMID:Glucocorticoid receptor-mediated cell cycle arrest is achieved through distinct cell-specific transcriptional regulatory mechanisms. 915 17

Loss of the p16INK4A gene by homozygous deletions or point mutations is attributed to the development of many types of cancers including leukemia. T cell acute lymphoblastic leukemias (T-ALLs) and B-cell ALLs show a remarkable rate of 75 and 20% homozygous deletion of this gene, respectively. Restoration of p16 expression in p16-deficient solid tumor cell lines results in a dramatic reduction of growth and maligant phenotype. To test the hypothesis that p16INK4A suppresses the growth of p16-deficient leukemias, we utilized a retroviral system to restore wild-type (wt) or mutant p16 protein expression. We tested the efficacy of our system by expressing the wt or mutant p16 genes in the osteosarcoma cell line, U20S, which lacks p16 and retains functional retinoblastoma protein (pRb). The wt p16 protein formed complexes with both cyclin-dependent kinases (CDK) 4 and 6 and inhibited U20S growth by 30-fold. The p16 mutants E120K and R144C formed complexes with CDK4 and CDK6 in cells and inhibited cell growth as effectively as wt p16 (20-fold) while the mutant proteins that did not complex with detectable levels of CDK4 or CDK6 only inhibited growth 0.25- and five-fold (G101W and D141, respectively) or not at all (H83Y and DA4). The COOH-terminal 'tail' of the wt p16 protein (amino acid residues 141-156), missing in mutant D141, enhanced the growth suppressive capability of p16. The amino acid substitutions in mutants G101W and H83Y not only disrupted CDK4 and CDK6 binding, but decreased the protein half-lives by two- and three-fold, respectively, compared to wt p16. The wt, but not mutant p16 genes, effectively inhibited the growth of T cell acute lymphoblastic (CEM) and myeloid leukemia (NB-4 and K562) cell lines that lacked the p16 gene, but retained functional pRb. Growth of the T-ALL cell line, HSB-2, which lacked both p16 and pRb, was not inhibited, indicating the growth suppression involved the pRb pathway. These results define regions critical for the function of p16 and demonstrate that restoration of wt p16 expression in p16-deficient leukemias significantly reverted their transformed phenotype and inhibited their growth.
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PMID:Inhibition of growth of human leukemia cell lines by retrovirally expressed wild-type p16INK4A. 932 88

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.
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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

Very little is known concerning the cytogenetic and molecular genetic changes of low-grade central osteosarcoma, a rare form of osteosarcoma. In the present study, we used comparative genomic hybridization (CGH) to screen for DNA sequence copy number aberrations in 10 samples from 6 patients: 7 typical low-grade central osteosarcomas, one low-grade (Grade II) central osteosarcoma, and two high-grade (III and IV) local recurrences of a low-grade central osteosarcoma Nine samples had aberrations. Six typical low-grade central osteosarcoma samples had a single DNA sequence copy number change per tumor. Three samples from more advanced tumors (a Grade II low-grade central osteosarcoma and local recurrences of Grade III and IV) had a mean of five changes per tumor. Recurrent changes affected these minimal common regions: +12q13-q14 (three tumors), +12p (two tumors), and +6p21.1-p21.3 (two tumors). Nine samples were analyzed for CDK4 and MDM2 expression and SAS amplification. One sample with a gain of chromosome 12 had a very strong expression of MDM2, strong expression of CDK4, and amplification of SAS. One sample with a gain of 12q13-q14 had strong expression of CDK4 and MDM2. Strong expression of CDK4 was found in two additional tumors; one had a gain of 12q13-q21, and the other had no changes in chromosome 12 by CGH. No alterations were detected in the CDK4, MDM2, and SAS panel in three other samples with no changes in chromosome 12 by CGH. In conclusion, the low number of DNA sequence copy number alterations reflects the relatively low malignancy of low-grade central osteosarcoma. This simplicity differs from the complex aberrations seen in conventional high-grade osteosarcomas.
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PMID:Comparative genomic hybridization of low-grade central osteosarcoma. 961 93

We have used c-Fos transgenic mice which develop osteosarcomas to determine the expression patterns of cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs) in different bone cell populations in order to define the potential mechanisms of c-Fos transformation. Immunohistochemical analysis in embryonic and early postnatal bone demonstrated that cyclin E and its kinase partner CDK2 were expressed specifically in bone-forming osteoblasts. Cyclin D1 expression was absent despite high levels of CDK4 and CDK6, and the CKI p27 was expressed in chondrocytes, osteoclasts, and at lower levels in osteoblasts. Following activation of the c-fos transgene in vivo and before overt tumor formation, cyclin D1 expression increased dramatically and was colocalized with exogenous c-Fos protein specifically in osteoblasts and chondrocytes, but not in osteoclasts. Prolonged activation of c-Fos resulted in osteosarcoma formation wherein the levels of cyclin D1, cyclin E, and CDKs 2, 4, and 6 were high in a wide spectrum of malignant cell types, especially in transformed osteoblasts. The CKI p27 was expressed at very high levels in bone-resorbing osteoclasts, and to a lesser extent in chondrocytes and osteoblasts. These in vivo observations suggest that cyclin D1 may be a target for c-Fos action and that elevation of cyclin D1 in osteoblasts which already express cyclin E/CDK2 and the cyclin D1 partners CDKs-4 and 6, may predispose cells to uncontrolled cell growth leading to osteosarcoma development. This study implicates altered cell cycle control as a potential mechanism through which c-Fos causes osteoblast transformation and bone tumor formation.
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PMID:Control of cell cycle gene expression in bone development and during c-Fos-induced osteosarcoma formation. 966 90

Osteosarcomas often suffer mutations of the RB (retinoblastoma) gene, with resultant inactivation of the pRb protein. pRb is one component in a cell-cycle control pathway that includes the p16 (encoded by the CDKN2A gene) and cyclin-dependent kinase 4 (cdk4, encoded by the CDK4 gene) proteins. We therefore sought to determine whether the CDKN2A and CDK4 genes were altered in those osteosarcomas that lacked RB inactivation. Twenty-one osteosarcomas (2 low-grade and 19 high-grade) were evaluated for homozygous deletion of the CDKN2A gene, CDK4 amplification, and allelic loss of the RB gene, as well as for expression of p16 and pRb proteins. Five high-grade osteosarcomas showed loss of p16 expression; four of these had homozygous CDKN2A deletions, and the fifth had a probable deletion obscured by numerous nonneoplastic, p16-immunopositive multinucleated giant cells. Thus, p16 immunohistochemistry may provide a sensitive means for assessing CDKN2A status. Twelve tumors (including the two low-grade osteosarcomas) were immunopositive for pRb, and nine tumors were immunonegative for pRb. Of the five cases with CDKN2A/p16 alterations, none had allelic loss of the RB gene and all expressed pRb, suggesting that each of these tumors had an intact RB gene. None of the tumors showed CDK4 amplification. No alterations were detected in the two low-grade osteosarcomas. This study suggests that CDKN2A is a tumor suppressor inactivated in osteosarcomas that lack RB mutations and that the p16-pRb cell-cycle control pathway is deregulated in a large number of high-grade osteosarcomas.
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PMID:CDKN2A gene deletions and loss of p16 expression occur in osteosarcomas that lack RB alterations. 966 76

The INK4A gene, localized to human chromosome 9p21, encodes p16INK4A, a tumor suppressor that functions at least in part through the inhibition of CDK4, a cyclin-dependent kinase encoded by a gene at 12q13. To examine INK4A gene alterations in uncultured samples of osteosarcoma and the relationship between INK4A and CDK4 alterations, we analyzed the INK4A and CDK4 genes in 87 specimens from 79 patients. INK4A deletion and CDK4 gene amplification were determined by quantitative Southern blot analysis. INK4A exon 2 was screened for mutation by polymerase chain reaction and single-strand conformational polymorphism analysis. Methylation at the CpG island in INK4A, associated with loss of p16INK4A expression, was assessed by Southern blot analysis using methylation-sensitive restriction enzymes. INK4A deletion (4/55) or rearrangement (1/55) was found in 5 of 55 cases. No INK4A exon 2 point mutations and methylation were detected. CDK4 gene amplification was found in 6 of 67 samples, but not in tumors with INK4A alteration. Amplification analysis of other genes at 12q13 (GLI, CHOP, HMGI-C and MDM2) in these 6 cases supports the view that CDK4 and MDM2 are independent targets for amplification, with variable amplification of the intervening region containing HMGI-C. Of 46 patients studied for both INK4A alterations and CDK4 amplification, the tumors in 22% contained one or the other. The prevalence of these alterations, in conjunction with the reported inactivation of RB in up to 80% of cases, suggests that genetic lesions deregulating the G1 to S cell cycle checkpoint may be an almost constant feature in the pathogenesis of osteosarcoma.
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PMID:CDK4 gene amplification in osteosarcoma: reciprocal relationship with INK4A gene alterations and mapping of 12q13 amplicons. 993

Amplification of genes in the 12q13-15 region occurs frequently in several malignancies including osteosarcoma. The products of these amplified genes are thought to provide cancer cells with a selective growth advantage; however, the specific gene(s) driving this amplicon is unknown. We have previously shown that the SAS gene is amplified in most parosteal osteosarcomas. In this study we analysed additional putative growth regulatory genes in this chromosomal region in 24 primary osteosarcoma specimens. CDK4 and SAS were coamplified in 6/6 parosteal tumors, and MDM2 was also amplified in 4/5 parosteal cases. In comparison, amplification occurred in only 2/16 classical intramedullary osteosarcomas and involved the SAS gene. Each amplified gene had a correspondingly elevated mRNA level. Four high grade intramedullary tumors had elevated mRNA expression of SAS, but did not exhibit gene amplification. Gene amplification/overexpression was not associated with metastatic disease and did not change markedly with tumor progression, as evidenced by analysis of sequential tumor specimens from eight patients. Three other genes in the 12q13-15 region (CDK2, WNT1 and WNT10b) were not amplified in any of the tumors. The different patterns of gene amplification and overexpression of CDK4, SAS and MDM2 in parosteal and intramedullary osteosarcomas may help explain the disparity in the biological behaviour of these two types of osteosarcoma.
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PMID:Co-amplification and overexpression of CDK4, SAS and MDM2 occurs frequently in human parosteal osteosarcomas. 998 29

The region q13-15 of chromosome 12 contains SAS, CDK4, and MDM2 genes that are rearranged or amplified in a variety of human sarcomas. This study evaluated SAS gene amplification, and MDM2 and CDK4 protein expression in 20 tumor samples of central low-grade osteosarcoma (16 primary, 3 recurrences, 1 lung metastasis). SAS amplification was analyzed by quantitative polymerase chain reaction (PCR), while from the same paraffin-embedded samples, MDM2 and CDK4 protein expression was evaluated by immunohistochemistry. MDM2 and CDK4 proteins were found strongly expressed in 35% and 65%, respectively, of the samples. SAS was found amplified in 15% of the samples. These findings indicate that these genes may be involved in tumorigenesis and progression of low-grade osteosarcoma.
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PMID:Analysis of SAS gene and CDK4 and MDM2 proteins in low-grade osteosarcoma. 1010 94


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