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)

Plasma cell tumor induction in mice by pristane is under multigenic control. BALB/c mice are susceptible to tumor development; whereas DBA/2 mice are resistant. Restriction fragment length polymorphisms between BALB/c and DBA/2 for Cdkn2a(p16) and Cdkn2b(p15), and between BALB/c and Mus spretus for Cdkn2c(p18(INK4c)) were used to position these loci with respect to the Pctr1 locus. These cyclin-dependent kinase (CDK) inhibitors mapped to a 6 cM interval of chromosome 4 between Ifna and Tal1. C.D2-Chr 4 congenic strains harboring DBA/2 alleles associated with the Pctr1 locus contained DBA/2 "resistant" alleles of the CDK4/CDK6 inhibitors p16 and p15. On sequencing p16 and p18 cDNAs, two different allelic variants within ankyrin repeat regions of p16 were found between BALB/c and DBA/2 mice. By using an assay involving PCR amplification and restriction enzyme digestion, allelic variants were typed among several inbred strains of mice. One of the variants, G232A, was specific to two inbred strains, BALB/cAn and ABP/Le, of mice and occurred in a highly conserved amino acid in both human and rat p16. When tested with wild-type (DBA/2) p16, both A134C and G232A BALB/c-specific variants of p16 were inefficient in their ability to inhibit the activity of cyclin D2/CDK4 in kinase assays with retinoblastoma protein, suggesting this defective, inherited allele plays an important role in the genetic susceptibility of BALB/c mice for plasmacytoma induction and that p16(INK4a) is a strong candidate for the Pctr1 locus.
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PMID:Cdkn2a, the cyclin-dependent kinase inhibitor encoding p16INK4a and p19ARF, is a candidate for the plasmacytoma susceptibility locus, Pctr1. 948 2

Anti-idiotype (anti-Id) antibody can induce tumor dormancy in a murine B lymphoma, BCL1, by its ability to induce cell cycle arrest and apoptosis (negative signaling). In human B lymphoma, there is accumulating evidence that the antitumor effect of anti-Id or several other B cell-reactive antibodies relates to their ability to act as agonists rather than conventional effector antibodies. In this study, we sought to elucidate the role of cyclins, cyclin-dependent kinases (CDKs), and their inhibitors in anti-IgM-induced cell cycle arrest to better understand the mechanisms underlying cancer dormancy. To accomplish this, we have performed in vitro studies with a human lymphoma cell line (Daudi) because its response to anti-Id (or anti-IgM) is similar to that of a BCL1 cell line, more reagents are available, and the results would be particularly pertinent to therapy of human B cell lymphomas. Our results show that cross-linking of membrane IgM on Daudi cells induces an arrest late in G1 and prevents pRb from becoming phosphorylated. The G1 arrest is correlated with an induction of the CDK inhibitor p21 and reduced CDK2 activity, although the level of CDK2 protein was not changed. Coprecipitation of CDK2 with p21 in anti-IgM-treated cells and the unchanged level of cyclin E suggest that p21 is responsible for the reduction of CDK2 activity and therefore blockade of the cell cycle. The induction of p21 was not accompanied by changes in p53 levels. As a result of the G1 block, cyclin A levels sharply declined by 24 h after anti-IgM treatment. There was no evidence for involvement of CDK4 or CDK6 in the blockade. These results provide evidence that membrane IgM cross-linking on Daudi cells induces expression of p21 and a subsequent inhibition of the cyclin E-CDK2 kinase complex resulting in a block to pRb phosphorylation and cell cycle arrest late in G1.
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PMID:Cancer dormancy: role of cyclin-dependent kinase inhibitors in induction of cell cycle arrest mediated via membrane IgM. 948 22

The cell cycle is regulated by various protein kinases, including cyclin-dependent kinases (CDKs). D-type CDKs, CDK4, and CDK6, phosphorylate retinoblastoma protein and are believed to regulate through the G1 phase of the cell cycle. CDK inhibitor p16INK4A has been characterized as binding CDK4 and CDK6 and as inhibiting phosphorylation of retinoblastoma protein by these CDKs. Thus p16INK4A is implicated in regulating the cell cycle at the G1 phase. The largest subunit of RNA polymerase II (pol II) contains an essential C-terminal domain (CTD). General transcription factor TFIIH, which contains CDK7, phosphorylates the CTD in vitro. The CTD phosphorylation is shown to be involved in transcriptional regulation in vivo and in vitro. Phosphorylation of RNA pol II CTD by TFIIH is thought to play an important role in transcriptional regulation. Here we report that p16INK4A associates with RNA pol II CTD and TFIIH. p16(INK4A) inhibited the CTD phosphorylation by TFIIH. These findings suggest that p16INK4A may regulate transcription via CTD phosphorylation in the cell cycle.
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PMID:Cyclin-dependent kinase inhibitor p16INK4A inhibits phosphorylation of RNA polymerase II by general transcription factor TFIIH. 948 60

Terminal differentiation of many cell types involves permanent withdrawal from the cell division cycle. The p18INK4c protein, a member of the p16/INK4 cyclin-dependent kinase (CDK) inhibitor family, is induced more than 50-fold during myogenic differentiation of mouse C2C12 myoblasts to become the predominant CDK inhibitor complexed with CDK4 and CDK6 in terminally differentiated myotubes. We have found that the p18INK4c gene expresses two mRNA transcripts--a 2.4-kb transcript, p18(L), and a 1.2-kb transcript, p18(S). In proliferating C2C12 myoblasts, only the larger p18(L) transcript is expressed from an upstream promoter. As C2C12 cells are induced to differentiate into permanently arrested myotubes, the abundance of the p18(L) transcript decreases. The smaller p18(S) transcript expressed from a downstream promoter becomes detectable by 12 h postinduction and is the predominant transcript expressed in terminally differentiated myotubes. Both transcripts contain coding exons 2 and 3, but p18(L) uniquely contains an additional noncoding 1.2-kb exon, exon 1, corresponding exclusively to the 5' untranslated region (5' UTR). The expression pattern of the shorter p18(S) transcript, but not that of the longer p18(L) transcript, correlates with terminal differentiation of muscle, lung, liver, thymus, and eye lens cells during mouse embryo development. The presence of the long 5' UTR in exon 1 attenuated the translation of p18(L) transcript, while its absence from the shorter p18(S) transcript resulted in significantly more efficient translation of the p18 protein. Our results demonstrate that during terminal muscle cell differentiation, induction of the p18 protein is regulated by promoter switching coupled with translational control.
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PMID:Coupled transcriptional and translational control of cyclin-dependent kinase inhibitor p18INK4c expression during myogenesis. 952 3

Depletion of guanine nucleotide pools after inhibition of inosine monophosphate dehydrogenase (IMPDH) potently inhibits DNA synthesis by arresting cells in G1 and has been shown to induce the differentiation of cultured myeloid and erythroid cell lines, as well as chronic granulocytic leukemic cells after blast transformation. Inhibitors of IMPDH are also highly effective as immunosuppressive agents. The mechanism underlying these pleiotropic effects of depletion of guanine nucleotides is unknown. We have examined the effects of mycophenolic acid (MPA), a potent IMPDH inhibitor, on the cell cycle progression of activated normal human T lymphocytes. MPA treatment resulted in the inhibition of pRb phosphorylation and cell entry into S phase. The expression of cyclin D3, a major component of the cyclin-dependent kinase (CDK) activity required for pRb phosphorylation, was completely abrogated by MPA treatment of T cells activated by interleukin-2 (IL-2) and leucoagglutinin (PHA-L), whereas the expression of cyclin D2, CDK6, and CDK4 was more mildly attenuated. The direct kinase activity of a complex immunoprecipitated with anti-CDK6 antibody was also inhibited. In addition, MPA prevented the IL-2-induced elimination of p27(Kip1), a CDK inhibitor, and resulted in the retention of high levels of p27(Kip1) in IL-2/PHA-L-treated T cells bound to CDK2. These results indicate that inhibition of the de novo synthesis of guanine nucleotides blocks the transition of normal peripheral blood T lymphocytes from G0 to S phase in early- to mid-G1 and that this cell cycle arrest results from inhibition of the induction of cyclin D/CDK6 kinase and the elimination of p27(Kip1) inhibitory activity.
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PMID:Effects of guanine nucleotide depletion on cell cycle progression in human T lymphocytes. 953

p15(INK4b) gene is an inhibitor of cyclin-dependent kinase (CDK) 4 and CDK6 whose expression is induced by transforming growth factor (TGF)beta. Recent reports suggest frequent methylation of the p15(INK4b) gene promoter in leukemias, and it has been proposed that this methylation could be necessary for leukemic cells to escape TGF beta regulation. We investigated the methylation status of p15(INK4b) gene in 53 myelodysplastic syndromes (MDS) cases, including nine that had progressed to acute myeloid leukemia (AML), using a recently described sensitive method where polymerase chain reaction (PCR) is preceded by bisulfite modification of DNA (methylation specific PCR). p15(INK4b) methylation was observed in 20 of 53 (38%) of the cases. Twenty of the 24 patients with greater than 10% bone marrow blasts had p15(INK4b) methylation (including all nine patients who had progressed to AML) as compared with none of MDS patients with <10% bone marrow blasts. No correlation between karyotypic abnormalities and methylation status was found. Patients with p15(INK4b) methylation had a worse prognosis, but the prognostic significance of p15(INK4b) methylation was no more found by multivariate analysis, due to its strong correlation to the percentage of marrow blasts. In 10 MDS cases, sequential DNA samples were available. In five of them, methylation of the p15(INK4b) gene was detected at leukemic transformation, but not at diagnosis. Our results showed that methylation of the p15(INK4b) gene in MDS is correlated with blastic bone marrow involvement and increases with disease evolution toward AML. It suggests that proliferation of leukemic cells might require an escape of regulation of the G1 phase of the cell cycle, and possibly of TGF beta inhibitory effect.
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PMID:Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. 953 10

There is an increasing interest in identifying potent cancer preventive and therapeutic agents against breast cancer. Silymarin, a flavonoid antioxidant isolated from milk thistle, exerts exceptionally high to complete anticarcinogenic effects in tumorigenesis models of epithelial origin. In this study, we investigated the anticarcinogenic effect of silymarin and associated molecular mechanisms, using human breast carcinoma cells MDA-MB 468. Silymarin treatment resulted in a significantly high to complete inhibition of both anchorage-dependent and anchorage-independent cell growth in a dose- and time-dependent manner. The inhibitory effects of silymarin on cell growth and proliferation were associated with a G1 arrest in cell cycle progression concomitant with an induction of up to 19-fold in the protein expression of cyclin-dependent kinase (CDK) inhibitor Cip1/p21. Following silymarin treatment of cells, an incremental binding of Cip1/p21 with CDK2 and CDK6 paralleled a significant decrease in CDK2-, CDK6-, cyclin D1-, and cyclin E-associated kinase activity with no change in CDK2 and CDK6 expression but a decrease in G1 cyclins D1 and E. Taken together, these results suggest that silymarin may exert a strong anticarcinogenic effect against breast cancer and that this effect possibly involves an induction of Cip1/p21 by silymarin, which inhibits the threshold kinase activities of CDKs and associated cyclins, leading to a G1 arrest in cell cycle progression.
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PMID:Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast cancer cells MDA-MB 468: induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinases and associated cyclins. 956 2

The pl6INK4a/MTS1 (p16) gene encodes a specific inhibitor of cyclin-dependent kinase (CDK)4 and CDK6. The p16 gene is frequently mutated or deleted in many types of cancer cell lines as well as in certain types of primary tumors. p16 knockout mice are viable but predisposed to sarcoma and B-cell lymphoma. To investigate the role of p16 in human soft-tissue sarcoma tumor progression, we examined the p16 gene by Southern blot analysis and PCR sequencing in 30 pairs of primary soft-tissue sarcomas and autologous normal tissue. Only one tumor sample showed possible rearrangement of the p16 gene. In contrast, Western blot analysis of the p16 protein in 20 pairs of samples showed decreased p16 expression in only 20% of the tumors but elevated p16 expression in 40% of the tumors when compared with the autologous normal controls. Overexpression of p16 was not concomitant with loss of the RB protein as is found in several other types of cancers, because more than one-half of the tumors with increased p16 expression also had high levels of RB protein. On the other hand, the p16 target protein CDK4 was overexpressed in at least 60% of the tumors. In the majority of cases, CDK4 overexpression accompanied elevated p16 and/or RB levels. Our results suggest that: (a) alteration of the p16 gene is infrequent in primary soft-tissue sarcoma; (b) Cdk4 may act as an oncogene in soft-tissue sarcoma; and (c) elevated p16 and RB levels might be the result of compensatory up-regulation of these proteins to counteract CDK4 overexpression in these tumors. Our results also suggest that it is more informative to examine aberrations in the "p16-CDK4/cyclin D-RB" pathway than to selectively examine individual components in this pathway when investigating genetic changes involved in human malignancy.
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PMID:Infrequent mutation of the p16/MTS1 gene and overexpression of cyclin-dependent kinase 4 in human primary soft-tissue sarcoma. 956 3

Prostate cancer (PCA) is the most common nonskin malignancy and the second leading cause of cancer deaths in United States males. One practical and translational approach to control PCA is to define a mechanism-based anticarcinogenic agent(s). Recently, we showed that silymarin, a flavonoid antioxidant isolated from milk thistle, possesses exceptionally high to complete protective effects against experimentally induced tumorigenesis. Because the epidermal growth factor receptor (erbB1) and other members of the erbB family have been shown to play important roles in human PCA, efforts should be directed to identify inhibitors of this pathway for PCA intervention. In this study, we assessed whether silymarin inhibits erbB1 activation and associated downstream events and modulates cell cycle regulatory proteins and progression, leading to growth inhibition of human prostate carcinoma DU145 cells. Treatment of serum-starved cells with silymarin resulted in a significant inhibition of transforming growth factor alpha-mediated activation of erbB1 but no change in its protein levels. Silymarin treatment of cells also resulted in a significant decrease in tyrosine phosphorylation of an immediate downstream target of erbB1, the adapter protein SHC, together with a decrease in its binding to erbB1. In the studies analyzing cell cycle regulatory molecules, silymarin treatment of cells also resulted in a significant induction of cyclin-dependent kinase inhibitors (CDKIs) Cip1/p21 and Kip1/p27, concomitant with a significant decrease in CDK4 expression, but no change in the levels of CDK2 and CDK6 and their associated cyclins E and D1, respectively. Cells treated with silymarin also showed an increased binding of CDKIs with CDKs, together with a marked decrease in the kinase activity of CDKs and associated cyclins. In additional studies, treatment of cells grown in 10% serum with anti-epidermal growth factor receptor monoclonal antibody clone 225 or different doses of silymarin also resulted in significant inhibition of constitutive tyrosine phosphorylation of both erbB1 and SHC but no change in their protein levels. Furthermore, whereas silymarin treatment resulted in a significant increase in the protein levels of both Cip1/p21 and Kip1/p27, monoclonal antibody 225 showed an increase only in Kip1/p27. These findings suggest that silymarin also inhibits constitutive activation of erbB1 and that the observed effect of silymarin on an increase in CDKI protein levels is mediated via inhibition of erbB1 activation only in the case of Kip1/p27; however, additional pathways independent of inhibition of erbB1 activation are possibly responsible for the silymarin-caused increase in Cip1/p21 in DU145 cells. In other studies, silymarin treatment also induced a G1 arrest in the cell cycle progression of DU145 cells and resulted in a highly significant to complete inhibition of both anchorage-dependent and anchorage-independent growth of DU145 cells in a dose- and time-dependent manner. Taken together, these results suggest that silymarin may exert a strong anticarcinogenic effect against PCA and that this effect is likely to involve impairment of erbB1-SHC-mediated signaling pathway, induction of CDKIs, and a resultant G1 arrest.
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PMID:A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. 958 34

In recent two years, a group of protein factors have been found to combine with the cyclin-dependent kinases (CDKs) and block the activation of cyclin/CDK complexes. They are named CDK inhibitors (CKIs) as p21, p16, p15, p27 and CDI1. The p21 and p27 have certain homology and can inhibit the activity of multiple CDKs; p16 and p15 have higher homology and can specifically combine with CDK4 and CDK6; and the combination specificity of CDI1 needs further research. The expression of p21 is regulated positively by p53. TGF-beta can upregulate the expression of p15 and the inhibitory activity of p27. The above findings demonstrate that CKIs are not only the regulators of CDKs' activity but also the direct linkers between cancer inhibitors and cell-cycle regulation.
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PMID:[Cyclin-dependent kinase inhibitors in mammal cells]. 959 31


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