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

The cyclin-dependent kinase inhibitors p16INK4/MTS1 and p15INK4B/MTS2 have been mapped to a region in chromosome 9 (921) that is deleted frequently in acute lymphoblastic leukemias and malignant gliomas. To gain insight into the functions of these inhibitors in lymphocytes and neuronal cells, we studied the expression of p15 and p16 during lymphocyte mitogenesis and neuronal differentiation. Expression of p15 was extinguished during lymphocyte activation, concomitant with an increase in retinoblastoma kinase activity. The differentiation of the embryonic teratocarcinoma cell line NT2 into postmitotic neurons (hNT) was associated with enhanced expression of p15 and p16 proteins. These findings suggest that p15 and p16 play a role in maintaining cell quiescence in lymphocytes and neuronal cells, respectively. Deletions of these genes may thus promote unrestrained growth.
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PMID:Expression of the p16 and p15 cyclin-dependent kinase inhibitors in lymphocyte activation and neuronal differentiation. 766 73

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

Protein hyper- or hypophosphorylation induced by okadaic acid (OA) treatment was examined using quiescent cultures of the BALB/MK-2 mouse epidermal keratinocytes. Treatment with OA enhanced the phosphorylation of five proteins with molecular weights of 65,000, 55,000, 50,000, 28,000 and 15,000 (p65, p55, p50, p28, and p15, respectively) and decreased that of two proteins with molecular weights of 22,000 and 20,000 (p22 and p20, respectively). The two major phosphorylated proteins, p65 and p55, were identified as type II and type I keratins, respectively, by immunoblotting and immunoprecipitation with keratin specific antibodies. Serine was the only phosphoamino acid residue in hydrolysates of the 32P-labeled keratins purified from OA-treated cells. Two-dimensional tryptic peptide maps of the phosphorylated keratins showed that the hyperphosphorylation was largely due to phosphorylation at several additional sites in both keratins. The hyperphosphorylation of keratins induced by OA treatment resulted in a drastic change in their solubility. This change closely correlated with reorganization of the keratin filament network, which finally collapsed into large perinuclear aggregates. Concomitantly the cells changed from a typical epithelial shape to a round shape. Of several protein kinase inhibitors tested, only staurosporine interfered with this OA-induced morphological change and reorganization of the keratin network.
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PMID:Hyperphosphorylation of keratins by treatment with okadaic acid of BALB/MK-2 mouse keratinocytes. 769 89

The cell cycle in mammalian cells is regulated by a series of cyclins and cyclin-dependent kinases (CDKs). The G1/S checkpoint is mainly dictated by the kinase activities of the cyclin D-CDK4 and/or cyclin D-CDK6 complex and the cyclin E-CDK2 complex. These G1 kinases can in turn be regulated by cell cycle inhibitors, which may cause the cells to arrest at the G1 phase. In T-cell hybridomas, addition of anti-T-cell receptor antibody results not only in G1 arrest but also in apoptosis. In searching for a protein(s) which might interact with Nur77, an orphan steroid receptor required for activation-induced apoptosis of T-cell hybridomas, we have cloned a novel human and mouse CDK inhibitor, p19. The deduced p19 amino acid sequence consists of four ankyrin repeats with 48% identity to p16. The human p19 gene is located on chromosome 19p13, distinct from the positions of p18, p16, and p15. Its mRNA is expressed in all cell types examined. The p19 fusion protein can associate in vitro with CDK4 but not with CDK2, CDC2, or cyclin A, B, E, or D1 to D3. Addition of p19 protein can lead to inhibition of the in vitro kinase activity of cyclin D-CDK4 but not that of cyclin E-CDK2. In T-cell hybridoma DO11.10, p19 was found in association with CDK4 and CDK6 in vivo, although its association with Nur77 is not clear at this point. Thus, p19 is a novel CDK inhibitor which may play a role in the cell cycle regulation of T cells.
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PMID:Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. 773 48

Cyclin and cyclin-dependent kinase (CDK) complexes play important roles in controlling the cell cycle. The CDK inhibitors (CDKIs) inhibit the kinase activities of the complexes and block transitions of the cell cycle. Recently several CDKI genes have been cloned, and evidence suggests that at least a couple of these may be tumor suppressor genes. In this study, the partial structure of a CDKI gene, p27/Kip1, was determined. In addition, a large number of human cancers (432 cases) and cancer cell lines (20 lines) were analyzed for alterations of the p27/Kip1 gene by Southern blot analysis and PCR/single-strand conformation polymorphism. The coding region of the p27/Kip1 gene consists of at least two exons and an intron of about 600 bp. In 140 tumors of various tissues and 18 transformed cell lines, no deletions or rearrangements of the gene were detected by Southern blot analysis using a part of the coding sequence as a probe. One polymorphism and one silent mutation were detected by PCR/single-strand conformation polymoprhism. The polymorphism was a nucleotide substitution of guanine for thymine (GTC-->GGC) at codon 109, resulting in an amino acid substitution of glycine for valine (Val-->Gly). In summary, no abnormalities of the p27/Kip1 gene were detected in human malignancies. Now, two groups of CDKIs are classified based on the structure of the proteins. One group includes the p15, p16, and p18 CDKIs, which have ankyrin repeat motifs. The p15 and p16 CDKI genes are very frequently mutated in a variety of cancers. The p27/Kip1 and p21 CDKIs belong to the other group. We reported previously that abnormalities of the p21 gene were very rare. The latter group of the CDKIs, including p27/Kip1 and p21, are rarely mutated in human malignancies.
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PMID:Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies. 775 74

Frequent homozygous deletions of the p16 (MTS1) gene encoding a cyclin-dependent kinase inhibitor were recently reported in various tumor cell lines including examples derived from lung cancers, but direct evidence for their occurrence in lung cancer patients has not been reported thus far. In the present study, alterations of p16 and/or p15, a p16-related cyclin-dependent kinase, were observed not only in lung cancer cell lines but also in the corresponding tumor specimens in vivo, excluding the possibility of in vitro artifacts. Interestingly, a clear specificity was also noted in terms of the affected histological subtype; i.e., only non-small cell lung cancers carried alterations (6 of 20 as compared to 0 of 20 small cell lung cancer cell lines).
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PMID:In vivo occurrence of p16 (MTS1) and p15 (MTS2) alterations preferentially in non-small cell lung cancers. 783 19

Cyclin and cyclin-dependent kinase (CDK) complexes play important roles in modulating the cell cycle. The CDK inhibitors (CDKIs) inhibit the kinase activities of these complexes and block the cell cycle. The p16/multiple tumor suppressor (MTS) 1/inhibitor of CDK4 (INK4) a/CDKN2 gene, a CDKI, is frequently deleted in a variety of human cancers. Recently another CDKI gene, p15/MTS2/INK4b, was cloned and localized to within 20 kb of the p16 gene. Moreover, a third CDKI gene, named p18/INK4c and having a high degree of protein homology to p16, has now been cloned. To elucidate the importance of these CDKI genes in non-small cell lung cancers (NSCLCs), we examined DNAs from 34 NSCLC samples for alterations in these genes by Southern blot and polymerase chain reaction (PCR)-single-strand conformational polymorphism (SSCP) analyses. Matched control normal tissues from the same individuals were also examined. Homozygous deletions of the p15 gene were found in three cases. Furthermore, comparative PCR analysis confirmed these deletions and suggested that one additional case had an abnormality of the p15 gene. Neither rearrangements nor deletions of the p18 gene were detected. By PCR-SSCP and direct sequencing of the aberrantly migrating bands, we detected only polymorphic nucleotide substitutions in both the p15 and p18 genes. In summary, the frequency of deletions of the p15 gene was 12% (four of 34 cases), and no point mutations in the p15 gene were detected in the NSCLCs. For the p18 gene, no abnormalities were detected. A previous analysis of these NSCLC samples for p16 gene alterations revealed that the three cases with homozygous deletions of the p15 gene also have homozygous deletions of the p16 gene.
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PMID:Molecular analysis of a family of cyclin-dependent kinase inhibitor genes (p15/MTS2/INK4b and p18/INK4c) in non-small cell lung cancers. 851 15

We have investigated the status of the MTS2 gene, encoding the cyclin-dependent kinase (CDK) inhibitor p15, in 32 glioblastomas. Semi-quantitative PCR identified 7 tumors in which the amplified material was 18.6% of controls and 7 in which was 48.0%, suggesting the occurrence of homozygous and hemizygous deletions, respectively. Single strand conformation polymorphism analysis identified one polymorphism but no mutations. We also expressed MTS2 and MTS1, encoding the contiguous and highly homologous CDK inhibitor p16, in U-87 human glioblastoma cells. Both genes, either separately or in combination, inhibit significantly the proliferation rate of U-87 cells but such inhibition is progressively lost. As a whole, the data assign a tumor suppressor role to p15 and confirm homozygous deletions as the favorite mechanism for the inactivation of MTS1 and MTS2 in glioblastomas.
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PMID:Deletion and transfection analysis of the p15/MTS2 gene in malignant gliomas. 852 10

5'-Deoxy-5'-methylthioadenosine phosphorylase (methylthioadeno-sine: ortho-phosphate methylthioribosyltransferase, EC 24.2.28; MTAP) plays a role in purine and polyamine metabolism and in the regulation of transmethylation reactions. MTAP is abundant in normal cells but is deficient in many cancers. Recently, the genes for the cyclin-dependent kinase inhibitors p16 and p15 have been localized to the short arm of human chromosome 9 at band p21, where MTAP and interferon alpha genes (IFNA) also map. Homozygous deletions of p16 and p15 are frequent malignant cell lines. However, the order of the MTAP, p16, p15, and IFNA genes on chromosome 9p is uncertain, and the molecular basis for MTAP deficiency in cancer is unknown. We have cloned the MTAP gene, and have constructed a topologic map of the 9p21 region using yeast artificial chromosome clones, pulse-field gel electrophoresis, and sequence-tagged-site PCR. The MTAP gene consists of eight exons and seven introns. Of 23 malignant cell lines deficient in MTAP protein, all but one had complete or partial deletions. Partial or total deletions of the MTAP gene were found in primary T-cell acute lymphoblastic leukemias (T-ALL). A deletion breakpoint of partial deletions found in cell lines and primary T-ALL was in intron 4. Starting from the centromeric end, the gene order on chromosome 9p2l is p15, p16, MTAP, IFNA, and interferon beta gene (IFNB). These results indicate that MTAP deficiency in cancer is primarily due to codeletion of the MTAP and p16 genes.
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PMID:Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme deficient in multiple different cancers. 865 Feb 44

Deregulation of cyclin, cyclin-dependent kinases (CDKs) and their inhibitors could have a pivotal role in the development of diverse human cancers. We examined the genetic status and the expression of CDK inhibitors (p21, p27, p16 and p15), CDK2 and cyclins (A, D1 and E) in eight gastric carcinoma cell lines, in comparison with the status of p53 gene alterations. All the cell lines (except MKN-28) that contained a p53 gene abnormality expressed very low or undetectable levels of p21 mRNA, while the cell lines (MKN-45 and -74) with wild-type p53 gene expressed high levels of p21 mRNA. An inverse correlation was found between the level of p21 mRNA and the expression of mRNAs for CDK2 and G1 cyclins. MKN-28 was an exception; it contained mutated p53, and expressed mRNAs for p21, CDK2 and G1 cyclins at high levels. Only MKN-45 and -74, with wild-type p53, expressed considerable levels of p21 protein. Homozygous deletion of the p16 and p15 genes was detected in two (MKN-45 and HSC-39) of the eight gastric carcinoma cell lines, p16 protein was not expressed in three cell lines (MKN-28, MKN-74 and KATO-III), as well as MKN-45 and HSC-39. Rearrangement of the p15 gene was found in TMK-1. Rearrangement of the p27 gene was detected in MKN-45, although the expression of p27 protein was well preserved in all the gastric carcinoma cell lines. The expression of pRb was also preserved in all the cell lines except KATO-III. No obvious correlation was observed between the p53 gene status and the expression of p27 and p16. These findings suggest that abnormal regulation of CDK2/cyclins and CDK inhibitors might be involved in deregulated growth of gastric carcinomas.
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PMID:Genetic status and expression of the cyclin-dependent kinase inhibitors in human gastric carcinoma cell lines. 879 88


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