Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new acute transforming type C retrovirus was isolated from mice inoculated with a virus stock obtained by iododeoxyuridine induction of methylcholanthrene-transformed C3H/10T1/2 mouse cells. This virus, designated 3611-MSV, transforms embryo fibroblasts and epithelial cells in culture and induces fibrosarcomas in vivo. 3611-MSV is replication defective, requiring a type C helper virus for propagation both in vitro and in vivo. By using endpoint transmission of 3611-MSV to MMCE C17 mouse and FRE 3A rat cells, several nonproductively transformed clonal cell lines have been derived. Pseudotype virus stocks obtained from such clones transform cells in vitro, are highly oncogenic in vivo, and exhibit host range and serological properties that are characteristic of their helper virus component. Analysis of viral antigen expression in 3611-MSV-transformed cells has led to the demonstration of a 90,000-molecular-weight (Mr) polyprotein and a 75,000-Mr probable cleavage product, both containing the amino-terminal murine leukemia virus gag gene proteins p15 and p12. In contrast to gene products of many previously described mammalian transforming viruses, 3611-MSV-encoded polyproteins lack detectable protein kinase activity, and 3611-MSV-transformed cells resemble chemically transformed cell line C3H/MCA-5, from which 3611-MuLV was originally derived, in that they do not exhibit elevated levels of phosphotyrosine. By using molecular hybridization the 3611-MSV transforming gene was found to be distinct from previously described mammalian cellular oncogenic sequences, including c-ras, c-abl, c-fes, c-fms, c-sis, and c-mos.
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PMID:New mammalian transforming retrovirus: demonstration of a polyprotein gene product. 630 Apr 62

A series of hybridomas have been isolated which produce monoclonal antibodies directed against polyprotein gene products of the Gardner, Snyder-Theilen, and McDonough strains of FeSV. Within these are representatives of several immunoglobulin classes including IgG1, IgG2a, IgG2b, and IgM. Antibody produced by one hybridoma recognizes immunologic determinants localized within an FeLV gag gene structural component (p15) common to polyproteins encoded by all three FeSV isolates whereas antibody produced by a second is specific for p30 determinants unique to P170gag-fms. Additional hybridomas secrete antibody directed against v-fes-encoded determinants common to the Gardner and Snyder-Theilen FeSV-encoded polyproteins. GA P110gag-fes and ST P85gag-fes immuno-precipitated by antibody directed against p15 exhibit tyrosine-specific protein kinase activity but lack such activity when precipitated by antibody specific for their acquired sequence (v-fes) components.
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PMID:Monoclonal antibodies to feline sarcoma virus gag and fes gene translational products. 630 16

A cell line, TBSV7, that produces noninfectious murine sarcoma virus (MuSV) in the absence of helper MuLV was isolated from TB cells infected with the supernatant of MuSV349 cells. These noninfectious MuSV particles with "immature" C-type virus morphology contain a 2.2 X 10(6)-Da genomic RNA and an uncleaved 62,000-Da gag precursor protein (Pr62). Neither viral envelope proteins (gp70, p15E, p12E) nor reverse transcriptase were detected in these virus particles. Pr62 was found to be phosphorylated in vivo and it could be phosphorylated in vitro with [gamma-32P]ATP, indicating that protein kinase was packaged in these noninfectious virions. In vitro processing of Pr62 to smaller molecular weight proteins could be achieved by the addition of Mo-MuLV and Nonidet P-40. The initial cleavage products were proteins with molecular weights of 38K (Pr38) and 27K (Pr27). Under optimum conditions Pr38 was cleaved to p30 and a protein band migrating with MuLV-p10, while Pr27 was cleaved to a 17,000-Da protein that migrated slower than MuLV-p15 and a protein band migrating with MuLV-p12. Pulse-chase experiments performed on TBSV7 cells superinfected with Mo-MuLV indicated that intracellular processing of Pr62 was much slower than that of Pr65. Cleavage protein products of Pr62 similar in size to the in vitro protein products were also detected in TBSV7 cells superinfected with MuLV.
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PMID:Isolation and characterization of a Mo-MuSV-transformed TB cell line that produces noninfectious MuSV particles with uncleaved gag protein which is processed in the presence of Mo-MuLV. 632 21

Formalin-fixed Staphylococcus aureus strain Cowan, bearing protein A, routinely used for the absorption of antigen-antibody complexes, was found to bind protein kinase activity from disrupted Moloney murine leukaemia virus (Mo-MuLV). The Wood strain of S. aureus lacking protein A also bound the kinase with similar efficiency. About 50% of the bound kinase activity, as detected by phosphorylation of casein using [gamma-32P]ATP, could be eluted from the bacterial preparation with buffer containing 0 X 5 M-KC1. Similar results were obtained with Moloney murine sarcoma virus (Mo-MuSV) strain 349 and ts110 MuSV(MuLV). The bacterial preparation was also found to bind casein kinase activity from cellular extracts of uninfected, Rauscher murine leukaemia virus (R-MuLV)-infected and Mo-MuLV-infected cells. Analysis of [3H]leucine-labelled proteins from purified virus showed selective binding to S. aureus of only two major labelled virus proteins. One virus component bound to S. aureus had the relative mobility of p15; the other polypeptide co-migrated with virus p10. Upon exposure to increased salt concentration, most of the p10 but very little of the p15 proteins were released. The S. aureus-binding proteins from ts110 Mo-MuSV and MuSV-349 revealed similar binding and elution patterns of p10 and p15 molecules. The p10 and protein kinase activity eluted from Mo-MuLV-absorbed bacteria were separated by gel filtration into a high molecular weight species, containing p10 and kinase activity, and a low molecular weight p10 monomer lacking enzymic activity.
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PMID:Binding of retrovirus-associated protein kinase and proteins to Staphylococcus aureus. 695 49

The transforming growth factor beta s (TGF-beta s) are a group of multifunctional growth factors that inhibit cell cycle progression in many cell types. The TGF-beta-induced cell cycle arrest has been partially attributed to the regulatory effects of TGF-beta on both the levels and activities of the G1 cyclins and their cyclin-dependent kinase partners. The ability of TGF-beta to inhibit the activity of these kinase complexes derives in part from its regulatory effects on the cyclin-dependent kinase inhibitors, p21/WAF1/Cip1, p27Kip1, and p15. Upon treatment of cells with TGF-beta, these three inhibitors bind to and block the activities of specific cyclin-cyclin-dependent kinase complexes to cause cell cycle arrest. Little is known, however, on the mechanism through which TGF-beta activates these cyclin-dependent kinase inhibitors. In the case of p21, TGF-beta treatment leads to an increase in p21 mRNA. This increase in p21 mRNA is partly due to transcriptional activation of the p21 promoter by TGF-beta. To further define the signaling pathways through which TGF-beta induces p21, we have performed a detailed functional analysis on the p21 promoter. Through both deletion and mutation analysis of the p21 promoter, we have defined a 10-base pair sequence that is required for the activation of the p21 promoter by TGF-beta. In addition, this sequence is sufficient to drive TGF-beta-mediated transcription from a previously nonresponsive promoter. Preliminary gel shift assays demonstrate that this TGF-beta responsive element binds specifically to several proteins in vitro. Two of these proteins are the transcription factors Sp-1 and Sp-3. These studies represent the initial steps toward defining the signaling pathways involved in TGF-beta-mediated transcriptional activation of p21.
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PMID:Functional analysis of the transforming growth factor beta responsive elements in the WAF1/Cip1/p21 promoter. 749 79

The cyclin-dependent kinase inhibitors known as p15, p16 and p18 have been suggested as candidates for tumour suppressor genes. We examined these genes for their alterations in 46 myeloid leukaemias and 15 myeloid leukaemia cell lines. p16 mRNA expression was studied in 41 myeloid leukaemias. The p15 and p16 genes were either deleted or mutated in myeloid leukaemia lines at a high frequency [6/15 (40%) for p15; 8/15 (53%) for p16] but alterations in primary myeloid leukaemias are much less frequent [2/46 (4%) for p15; 3/46 (6%) for p16]. Alterations of p18 were not found in any of the samples. 13 primary myeloid leukaemia samples had negligible levels of p16 mRNA. In summary, the deletions of p15 and p16 genes identified in the myeloid leukaemia cell lines probably occurred during their in vitro immortalization. Alterations of the p16 or p15 gene only occurred in primary acute myeloid leukaemia samples that were of mixed myeloid/lymphoid lineage (CD19/CD20-positive acute myeloid leukaemia [AML], CD2/CD19-positive AML, and lymphoid blastic crisis of chronic myeloid leukaemia). Further studies are required to determine if the absence of mRNA expression results from inactivation of the p16 gene.
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PMID:Structural integrity of the cyclin-dependent kinase inhibitor genes, p15, p16 and p18 in myeloid leukaemias. 757 21

Transforming growth factor beta (TGF-beta) causes growth arrest in the G1 phase in many cell types. One probable pathway for this growth inhibition is through the TGF-beta-mediated up-regulation of the cyclin-dependent kinase (CDK) inhibitor p15INK4B, which specifically inhibits the enzymatic activities of CDK4 and CDK6. An active cyclin D-CDK4/6 complex is required for pRb phosphorylation to allow the cell cycle to progress from G1 to S phase. To study the molecular mechanism of the p15INK4B induction by TGF-beta, we isolated a 780-base pair promoter sequence of the human p15 gene and inserted this fragment upstream of a luciferase reporter gene. When this construct was transiently transfected into HaCaT cells, luciferase activity was induced more than 10-fold upon TGF-beta treatment, indicating that the induction of p15INK4B expression by TGF-beta is partly exerted at the transcription level. Promoter deletion analysis revealed that the sequence from -110 to -40 relative to the transcription start site is capable of conferring the 10-fold induction by TGF-beta. Within this region there are three Sp1 consensus sites. Mutation of one of these sites, GGGGCGGAG, substantially reduced both the induction by TGF-beta and the basal promoter activity, whereas mutations in the other two Sp1 sites and the spacer sequences had little effect. In addition, gel mobility shift assay indicates that the transcription factors Sp1 and Sp3 bind to this Sp1 site. Taken together, these data suggest that a specific Sp1 consensus site is involved in the mediation of TGF-beta induction as well as the basal promoter activity of the p15 gene and that Sp1 and Sp3 transcription factors might be involved in this regulation.
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PMID:Transforming growth factor beta activates the promoter of cyclin-dependent kinase inhibitor p15INK4B through an Sp1 consensus site. 759 8

A newly recognized family of proteins that inhibit cyclin-dependent kinases (CDKs) termed cyclin-dependent kinase inhibitors (CDKI) have an important role in regulation of cell-cycle progression. A subfamily of these CDKIs (p15INK4B/MTS2, p16INK4/MTS1, and p18) have a high degree of structural and functional homology and are candidate tumor-suppressor genes. We evaluated the mutational status of the p15, p16, and p18 genes in 103 childhood acute lymphoblastic leukemia (ALL) samples and correlated these results with both their clinical data and additional results concerning their loss of heterozygosity in the region of the p15/p16 genes. Homozygous deletions of the p16 gene occurred extremely frequently in T-ALLs (17/22; 77%), and it was also frequent in precursor-B ALLs (12/81; 15%). Homozygous deletions of the p15 gene were also very frequent in T-ALLs (9/22; 41%), and it occurred in 5 of 81 (6%) precursor-B ALL samples. No deletions of p18 was found in any of the 103 ALL samples. Also, no point mutations of the p15, p16, and p18 genes were detected. We correlated p15/p16 alterations at diagnosis with their clinical characteristics as compared with 2,927 other patients treated similarly. Those with p15/p16 alterations were older; had higher white blood cell counts, often with T-cell ALL phenotype; and more frequently had a mediastinal mass at presentation; but they had the same nonremission, relapse, and survival rates at 5 years as did those patients whose blast cells did not have a p15/p16 deletion. To better understand the extent of alterations affecting chromosome 9p21 (location of the p15/p16 genes), loss of heterozygosity (LOH) was examined at D9S171, which is about 1 megabase proximal to the p15/p16 genes. LOH was detected in 15 of 37 (41%) informative samples. Interestingly, of the 24 informative samples that had no detectable alteration of the p15/p16 genes, 7 samples (29%) had LOH at D9S171. In summary, we show in a very large study that p15 and p16, but not p18, CDKI genes are very frequently altered in ALL; those with p15/p16 alterations are more frequently older children, have higher white blood cells at presentation, and often have a T-cell ALL phenotype. The LOH analysis suggests that another tumor-suppressor gene important in ALL also is present on chromosome 9p21.
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PMID:Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood. 760 4

We have analyzed the mechanisms underlying stimulation of transcription by the activator GAL4-AH and the recombinant coactivator p15 (PC4). We show that p15 binds to both double-stranded and single-stranded DNA. Analyses of deletion mutants correlates binding to double-stranded DNA with the ability to mediate activator-dependent transcription. Consistent with this finding, phosphorylation of p15 by casein kinase II inhibits binding to double-stranded DNA and the activity of p15. The functional characterization suggests interactions of p15 with both DNA and components of the TFIID complex. GAL4-AH functions in concert with p15 during formation of TFIIA-TFIID-promoter (DA) complexes, as concluded from order-of-addition experiments. At limiting TFIID concentrations, the number of DA complexes is enhanced. The activator also stimulates transcription moderately after DA complex formation, independently of the concentrations of general transcription factors.
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PMID:The coactivator p15 (PC4) initiates transcriptional activation during TFIIA-TFIID-promoter complex formation. 762 53

Four cyclin-dependent kinase inhibitors called p15, p16, p21 and p27 have been identified in mammals. Because these proteins participate in the control of cell cycle, they are potential targets for somatic mutations during carcinogenesis. In order to document the prevalence of p15 and p16 alterations in gliomas, we looked for loss of heterozygosity of chromosome 9p where these genes are localized. Allelic losses were observed in 31 of 44 investigated cases. In all cases they involved the p15/p16 locus. We then looked for mutations in the p16 and p15 genes in 46 gliomas. A total of three DNA variants were observed which were all present in the matched constitutional DNA. They may be unrelated to tumor development. A single somatic mutation was detected. It involved a C to G substitution in codon 93 of p16 and is predicted to change a threonine into an arginine. Taken together, these data indicate that inactivation by point mutation of these two cyclin-dependent kinase inhibitors is uncommon in glial tumor carcinogenesis, but that there may be a tumor suppressor gene on 9p in the vicinity of p16 and p15 genes.
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PMID:Frequent loss of heterozygosity on chromosome 9, and low incidence of mutations of cyclin-dependent kinase inhibitors p15 (MTS2) and p16 (MTS1) genes in gliomas. 763 Jun 44


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