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)

Cyclins are key regulatory proteins that, in concert with cyclin-dependent protein kinase subunits (cdks), function to govern critical transitions and/or restriction points during the course of cell cycle progression. Recently, a number of putative mammalian G1 cyclins have been characterized at the molecular level; however, the specific activities of the cyclin/cdk complexes and the precise biochemical pathways regulated by the G1 cyclins remain to be elucidated. In the present study we identify a novel cyclin-like protein in pediatric bone and extremity tumors that appears to be related to, but is clearly distinct from, previously identified members of the cyclin D family, as determined by its profile of antibody cross-reactivity, apparent molecular size, chromatographic behavior, physicochemical properties, and pattern of peptide mapping. This 46-kDa cyclin-like protein, tentatively designated p46cyclin X, is first expressed in synchronized MG-63 osteosarcoma cells in mid-G1, well after the induction of p36cyclin D1, yet prior to the induction of cyclins E and A. Northern analysis, utilizing an oligonucleotide probe complementary to an epitope shared by cyclins D1, D2, and X, detected a novel mRNA species, the appearance of which correlates with p46cyclin X expression. The p46cyclin X protein in Ewing's sarcomas and Wilms' tumors is electrophoretically and chromatographically distinct from both p36cyclin D1 and p34cyclin D2. Moreover, the p46cyclin X protein is 1) precipitated by p9Ckshs1-agarose beads, 2) physically associated with p33cdk2, and 3) autophosphorylated in in vitro kinase reactions. Taken together with the biochemical data, the temporal expression of the p46cyclin X/p33cdk2 kinase system is suggestive of a potential role in regulating latter G1 events (i.e. START) in the commitment to S phase.
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PMID:Identification of a novel cyclin-like protein in human tumor cells. 838 71

Originally identified as a 'mitotic cyclin', cyclin A exhibits properties of growth factor sensitivity, susceptibility to viral subversion and association with a tumor-suppressor protein, properties which are indicative of an S-phase-promoting factor (SPF) as well as a candidate proto-oncogene. Other recent studies have identified human cyclin D1 (PRAD1) as a putative G1 cyclin and candidate proto-oncogene. However, the specific enzymatic activities and, hence, the precise biochemical mechanisms through which cyclins function to govern cell cycle progression remain unresolved. In the present study we have investigated the coordinate interactions between these two potentially oncogenic cyclins, cyclin-dependent protein kinase subunits (cdks) and the Rb tumor-suppressor protein. The distribution of cyclin D isoforms was modulated by serum factors in primary fetal rat lung epithelial cells. Moreover, cyclin D1 was found to be phosphorylated on tyrosine residues in vivo and, like cyclin A, was readily phosphorylated by pp60c-src in vitro. In synchronized human osteosarcoma cells, cyclin D1 is induced in early G1 and becomes associated with p9Ckshs1, a Cdk-binding subunit. Immunoprecipitation experiments with human osteosarcoma cells and Ewing's sarcoma cells demonstrated that cyclin D1 is associated with both p34cdc2 and p33cdk2, and that cyclin D1 immune complexes exhibit appreciable histone H1 kinase activity. Immobilized, recombinant cyclins A and D1 were found to associate with cellular proteins in complexes that contain the p105Rb protein. This study identifies several common aspects of cyclin biochemistry, including tyrosine phosphorylation and the potential to interact directly or indirectly with the Rb protein, that may ultimately relate membrane-mediated signaling events to the regulation of gene expression.
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PMID:Two potentially oncogenic cyclins, cyclin A and cyclin D1, share common properties of subunit configuration, tyrosine phosphorylation and physical association with the Rb protein. 847 54

A mathematical model integrating the roles of cyclin D, cdk4, cyclin E, cdk2, E2F and RB in control of the G1 phase of the cell cycle is described. Experimental results described with murine embryo fibroblasts (MEFs), either Rb+/+ or Rb-/-, and with the RB-deficient osteosarcoma cell line, Saos-2, served as the basis for the formulation of this mathematical model. A model employing the known interactions of these six proteins does not reproduce the experimental observations described in the MEFs. The appropriate modelling of G1 requires the inclusion of a sensing mechanism which adjusts the activity of cyclin E/cdk2 in response to both RB concentration and growth factors. Incorporation of this sensing mechanism into the model allows it to reproduce most of the experimental results observed in Saos-2 cells, Rb-/- MEFS, and Rb+/+ MEFs. The model also makes specific predictions which have not been tested experimentally.
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PMID:A mathematical model of the regulation of the G1 phase of Rb+/+ and Rb-/- mouse embryonic fibroblasts and an osteosarcoma cell line. 937 29

The retinoblastoma family proteins pRB, p107, and p130 are phosphorylated and released from E2Fs in the late G(1) phase of the cell cycle. This phosphorylation is thought to contribute to the derepression of E2F-responsive genes and to be mediated, in part, by Cdk4 and Cdk6. Evidence that Cdk4/6 activity is inhibited by p16(INK4A) in most pRB(-) cells suggests that p107 and p130 may be underphosphorylated and remain associated with E2Fs during G(1)-S progression in cells that lack pRB. To examine this, we evaluated the cell cycle-dependent phosphorylation and E2F binding abilities of p107 and p130 in pRB(-), p16(+) Saos-2 osteosarcoma cells. p130, but not p107, was phosphorylated and released from E2F-4 in late G(1) and S phase cells, although p130 phosphorylation differed qualitatively in these and other pRB(-), p16(+) cells as compared with pRB(+), p16(-) cell types. p130 phosphorylation occurred in the absence of cyclin D-Cdk4/6 complexes, coincided with cyclin E- and Cdk2-associated kinase activity, and was prevented by expression of dominant negative Cdk2. Moreover, dominant negative Cdk2 prevented the dissociation of endogenous p130-E2F-4 complexes and inhibited E2F-4-dependent transcription. These findings show that p130 can be phosphorylated and functionally inactivated in a Cdk2-dependent process, and they highlight the involvement of distinct Cdks in the regulation of different pRB family proteins.
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PMID:Cdk2-dependent phosphorylation and functional inactivation of the pRB-related p130 protein in pRB(-), p16INK4A(+) tumor cells. 1090 46

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

The human INK4a gene locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4a) and p14(ARF), which are frequently inactivated in human cancer. Whereas p16(INK4a) acts through engagement of the Rb-cdk4/6-cyclin D pathway, both the pro-apoptotic and cell cycle-regulatory functions of p14(ARF) were shown to be primarily dependent on the presence of functional p53. Recent reports have also implicated p14(ARF) in p53-independent mechanisms of cell cycle regulation and apoptosis induction, respectively. To further explore the pro-apoptotic function of p14(ARF) in relation to functional cellular p53, we constructed a replication-deficient adenoviral vector for overexpression of p14(ARF) (Ad-p14(ARF)). As expected, Ad-p14(ARF) efficiently induced apoptosis in p53/Rb wild-type U-2OS osteosarcoma cells at low multiplicities of infection. Interestingly, Ad-p14(ARF) also induced apoptosis in both p53-deleted SAOS-2 osteosarcoma cells and HCT116 colon cancer cells with a bi-allelic knock-out of p53 (HCT116-p53(-/-)). Similarly, adenovirus-mediated overexpression of p14(ARF) induced apoptosis in p53/Bax-mutated DU145 prostate cancer cells as well as in HCT116 cells devoid of functional Bax (HCT116-Bax(-/-)). Restoration of Bax expression by retroviral gene transfer in DU145 cells did not further enhance p14(ARF)-triggered cell death. Infection with Ad-p14(ARF) induced activation of mitochondrial permeability shift transition, caspase activation and apoptotic DNA fragmentation irrespective of the presence or absence of either Bax or functional cellular p53. Nevertheless, overexpression of the anti-apoptotic Bcl-2 homolog Bcl-x(L) markedly inhibited p14(ARF)-induced apoptosis. This may indicate that p14(ARF) triggers a so far unknown activator of mitochondrial apoptosis which can be inhibited by Bcl-2 but which acts either independently or downstream of Bax. Taken together, this report demonstrates the participation of signaling pathways apart from the p53/Mdm-2 rheostat and Bax in p14(ARF)-mediated apoptosis.
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PMID:Adenovirus-mediated overexpression of p14(ARF) induces p53 and Bax-independent apoptosis. 1208 30

Recently cloned leukotactin-1 (Lkn-1) that belongs to CC chemokine family has not been characterized. To understand the intracellular events following Lkn-1 binding to CCR1, we investigated the activities of signaling molecules in response to Lkn-1 in human osteogenic sarcoma cells expressing CCR1. Lkn-1-stimulated cells showed elevated phosphorylation of extracellular signal-related kinases (ERK1/2) with a distinct time course. ERK activation was peaked in 30 min and 12 h showing biphasic activation of ERK. Pertussis toxin, an inhibitor of G(i)/G(o) protein, and phospholipase C (PLC) inhibitor blocked Lkn-1-induced activation of ERK. Protein kinase C delta (PKC delta) specific inhibitor rottlerin inhibited ERK activation in Lkn-1-stimulated cells. The activities of PLC and PKC delta were also enhanced by Lkn-1 stimulation. Dominant negative Ras inhibited activation of ERK. Immediate early response genes such as c-fos and c-myc were induced by Lkn-1 stimulation. Lkn-1 affected the cell cycle progression by cyclin D(3) induction. These results suggest that Lkn-1 activates the ERK pathway by transducing the signal through G(i)/G(o) protein, PLC, PKC delta and Ras, and it may play a role for cell proliferation, differentiation, and regulation of gene expression for other cellular processes.
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PMID:Leukotactin-1-induced ERK activation is mediated via Gi/Go protein/PLC/PKC delta/Ras cascades in HOS cells. 1275 39

Aberrations of chromosome 9 p21-22 are involved in the genesis of many forms of cancer. The gene p16 and p15 have been assigned to this region. Both p16 and p15 are an inhibitor of cyclin D-cdk4,cyclin D-cdk6 complex and have been implicated in a wide variety of cancer types, including the germline of patients with familial melanoma. In order to investigate and compare the status of p16,p15 gene in primary tumors and cell lines, we examined 357 primary tumors and 29 cell lines derived from diverse tumor types. In addition to analysis of these primary tumors and cell lines, blood specimens from 91 patients either with sporadic multiple cancers or from cancer-prone families were also analyzed. The data showed the following: 1) Homozygous deletions of p16,p15 were comparatively rare and far less common than previously reported, although hemizygous deletions were observed in a significant fraction of many tumor types; 2) the incidence of p16,p15 deletions (either homozygous deletions or heterozygous deletions) varied significantly among different tumor types; 3) most deletions involved in both p16 and p15 genes; 4) sequence variations in the coding sequence of p16,p15 were comparatively rare among these tumor types, though mutations and polymorphisms were identified; 5) some tumors which showed LOH at 9p, containing p16 and p15 gene, did not show deletions or point mutations in the p16,p15 gene. 6) In a subset of retinoblastoma and osteosarcoma where no Rb gene mutations were present a significant fraction was found to contain p16,p15 gene deletions.
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PMID:Deletions and point mutations of p16,p15 gene in primary tumors and tumor cell lines. 1289 91

Transgenic mice overexpressing the c-Fos oncoprotein develop osteosarcomas that are associated with deregulated expression of cell cycle genes. Here we have generated osteoblast cell lines expressing c-fos under the control of a tetracycline-regulatable promoter to investigate the role of c-Fos in osteoblast cell cycle control in vitro. Three stable subclones, AT9.2, AT9.3, and AT9.7, derived from MC3T3-E1 mouse osteoblasts, expressed high levels of exogenous c-fos mRNA and protein in the absence of tetracycline. Functional contribution of ectopic c-Fos to AP-1 complexes was confirmed by electromobility shift assays and transactivation of AP-1 reporter constructs. Induction of exogenous c-Fos in quiescent AT9.2 cells caused accelerated S-phase entry following serum stimulation, resulting in enhanced growth rate. Ectopic c-Fos resulted in increased expression of cyclins A and E protein levels, and premature activation of cyclin A-, cyclin E-, and cyclin-dependent kinase (CDK) 2-associated kinase activities, although cyclin D levels and CDK4 activity were not affected significantly in these cell lines. The enhanced CDK2 kinase activity was associated with a rapid, concomitant dissociation of p27 from CDK2-containing complexes. Deregulated cyclin A expression and CDK2 activity was also observed in primary mouse osteoblasts overexpressing c-Fos, but not in fibroblasts, and c-Fos transgenic tumor-derived osteosarcoma cells constitutively expressed high levels of cyclin A protein. These data suggest that overexpression of c-Fos in osteoblasts results in accelerated S phase entry as a result of deregulated cyclin A/E-CDK2 activity. This represents a novel role for c-Fos in osteoblast growth control and may provide c-Fos-overexpressing osteoblasts with a growth advantage during tumorigenesis.
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PMID:Accelerated cell cycle progression in osteoblasts overexpressing the c-fos proto-oncogene: induction of cyclin A and enhanced CDK2 activity. 1469 50

A high percentage of tumor cells bear mutations in the Rb tumor suppressor gene. They have high levels of the cdk inhibitor p16(ink4a) and no cyclin D/cdk4-6 complexes. Although p16 is known not to arrest the proliferation of Rb-negative cells, it is not known whether its presence affects how their cycle progresses, how E2F-dependent transcription is modulated, and whether and how Rb-related proteins are inactivated. We have assessed the relevance of p16(ink4a) for cell cycle progression of these cells. Using SaOS2 osteosarcoma cells as a model, we find that downregulation of p16(ink4a) by RNAi and reconstitution of active cyclin D/cdk4 complexes does not affect progression of the cycle of these cells or expression of E2F-dependent genes. Rb-negative tumor cells can functionally inactivate Rb-related proteins in G(1)/S transition independently of their p16(ink4a) status. Furthermore, Rb-negative tumor cells do not arrest when cdk1, cdk2 or cdk3 are inhibited by RNAi, independently of their p16(ink4a) status, and combined inhibition of these cdks is also not enough to arrest their cell cycle. However, cell cycle progression of Rb-negative tumor cells is sensitive to complete cdk inhibition, as it is arrested by the chemical cdk inhibitor roscovitine and the biological cdk inhibitor p27. These results suggest that, despite their lack of cyclin D-containing complexes, Rb-negative tumor cells, like normal untransformed cells, take advantage of the high degree of redundancy of cdks for their cell cycle progression.
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PMID:CDK redundancy guarantees cell cycle progression in Rb-negative tumor cells independently of their p16 status. 1860 73


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