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)

After mild ischemic insults, many neurons undergo delayed neuronal death. Aberrant activation of the cell cycle machinery is thought to contribute to apoptosis in various conditions including ischemia. We demonstrate that loss of endogenous cyclin-dependent kinase (Cdk) inhibitor p16(INK4a) is an early and reliable indicator of delayed neuronal death in striatal neurons after mild cerebral ischemia in vivo. Loss of p27(Kip1), another Cdk inhibitor, precedes cell death in neocortical neurons subjected to oxygen-glucose deprivation in vitro. The loss of Cdk inhibitors is followed by upregulation of cyclin D1, activation of Cdk2, and subsequent cytoskeletal disintegration. Most neurons undergo cell death before entering S-phase, albeit a small number ( approximately 1%) do progress to the S-phase before their death. Treatment with Cdk inhibitors significantly reduces cell death in vitro. These results show that alteration of cell cycle regulatory mechanisms is a prelude to delayed neuronal death in focal cerebral ischemia and that pharmacological interventions aimed at neuroprotection may be usefully directed at cell cycle regulatory mechanisms.
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PMID:Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death. 1143 80

In response to phosphate limitation, Saccharomyces cerevisiae induces transcription of a set of genes important for survival. A phosphate-responsive signal transduction pathway mediates this response by controlling the activity of the transcription factor Pho4. Three components of this signal transduction pathway resemble those used to regulate the eukaryotic cell cycle: a cyclin-dependent kinase (CDK), Pho85; a cyclin, Pho80; and a CDK inhibitor (CKI), Pho81. Pho81 forms a stable complex with Pho80-Pho85 under both high- and low-phosphate conditions, but it only inhibits the kinase when cells are starved for phosphate. Pho81 contains six tandem repeats of the ankyrin consensus domain homologous to the INK4 family of mammalian CKIs. INK4 proteins inhibit kinase activity through an interaction of the ankyrin repeats and the CDK subunits. Surprisingly, we find that a region of Pho81 containing 80 amino acids C terminal to the ankyrin repeats is necessary and sufficient for Pho81's CKI function. The ankyrin repeats of Pho81 appear to have no significant role in Pho81 inhibition. Our results suggest that Pho81 inhibits Pho80-Pho85 with a novel motif.
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PMID:Functional analysis of the cyclin-dependent kinase inhibitor Pho81 identifies a novel inhibitory domain. 1153 56

The inhibitors of cyclin-dependent kinase (CDK) 4 (INK4) bind CDK4/6 to prevent their association with D-cyclins and G(1) cell cycle initiation and progression. We report here that among the seven CDK inhibitors, p18(INK4c) played an important role in modulating TCR-mediated T cell proliferation. Loss of p18(INK4c) in T cells led to hyperproliferation in response to CD3 stimulation. p18(INK4c)-null mice developed lymphoproliferative disorder and T cell lymphomas. Expression of IL-2, IL-2R-alpha, and the major G(1) cell cycle regulatory proteins was not altered in p18-null T cells. Both FK506 and rapamycin efficiently inhibited proliferation of p18-null T cells. In activated T cells, p18(INK4c) remained constant, and preferentially associated with and inhibited CDK6 but not CDK4. We propose that p18(INK4c) sets an inhibitory threshold in T cells and one function of CD28 costimulation is to counteract the p18(INK4c) inhibitory activity on CDK6-cyclin D complexes. The p18(INK4c) protein may provide a novel target to modulate T cell immunity.
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PMID:An important role of CDK inhibitor p18(INK4c) in modulating antigen receptor-mediated T cell proliferation. 1154 16

Central to many cancers is the aberrant expression of genes that regulate the cell cycle including the cyclin-dependent kinase inhibitors known as p15INK4b and p16INK4a, p14ARF and the retinoblastoma (RB) protein. We performed a detailed analysis of the methylation status of these genes by methylation specific polymerase chain reaction (MSP) in tumor cells of 35 adult T-cell leukemia/lymphoma (ATL) patients. We found in nine of 35 cases (26%) at least one gene methylated. The frequency of p15INK4b methylation was 7 of 35 (20%). The incidence of methylation of p14ARF and p16INK4a was two of 35 (6%) and one of 35 (3%), respectively. The RB gene was not found to be methylated in any of the ATL samples. The data indicate that inactivation of these cell cycle regulatory genes by hypermethylation is important in the development of ATL.
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PMID:Methylation analysis of cell cycle control genes in adult T-cell leukemia/lymphoma. 1169 28

The INK4A/ARF/INK4B locus, conserved in mammals, encodes three polypeptides that regulate cell proliferation via the pRb and p53 tumour suppressor pathways. The locus is mutated in many cancers. The related, tandemly-linked INK4A and INK4B genes encode the p16(INK4A) and p15(INK4B) members of the INK4 family of cyclin-dependent kinase inhibitors which block phosphorylation of pRb, whereas the third product, ARF, derived from an alternative reading frame of INK4A, regulates p53 activity. We assessed the status of this unusual locus in the puffer fish, Fugu rubripes, and identified two INK4 genes using degenerate PCR and hybridization analyses. Sequence conservation and conservation of synteny between human and Fugu predict one gene to be an INK4A or INK4B homologue and the other an INK4D homologue. Analysis of the Fugu INK4A/B gene and the surrounding 40-kb of genomic DNA did not reveal the presence of any ARF-encoding potential or another related INK4 gene. We conclude that the gene duplication event that generated adjacent INK4A and INK4B genes and the association of ARF with the ancestral INK4A gene occurred after the divergence of the lineage leading to mammals from fish. Thus, unlike mammals, the fish p53 and pRb tumour suppressor pathways are not regulated by a single locus.
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PMID:One INK4 gene and no ARF at the Fugu equivalent of the human INK4A/ARF/INK4B tumour suppressor locus. 1170 76

In the past decade, the discovery and characterization of cyclin-dependent kinases (CDKs), the engine cores of the cell cycle machinery, have advanced our understanding of the cell cycle. Both positive and negative regulators of CDKs have been characterized, accelerating the important research to unravel the mechanisms of the cell cycle disease--cancer. Cancer can originate from overexpression of positive regulators, such as cyclins, or from underexpression of negative regulators, such as CDK inhibitors (CKIs). CKIs are the focus of much cancer research because they are capable of controlling cell cycle proliferation--the Holy Grail for cancer treatment. CDKs can be inactivated by several mechanisms:, (i) by association with CKIs including p16 (INK4a), p15 (INK4b), p21 (Cip1), p27 (Kip1), and p57 (Kip2), (ii) by disassociation from their cyclin regulatory unit, (iii) by dephosphorylation of a conserved threonine residue in the T-loop, and (iv) by adding inhibitory phosphate. Here we discuss what is known about each mechanism with a hope that these insights will become useful in developing strategies to eliminate cancer in the future.
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PMID:Negative regulators of cyclin-dependent kinases and their roles in cancers. 1176 87

Cellular senescence has been proposed to be an in vitro and in vivo block that cells must overcome in order to immortalize and become tumorigenic. To characterize these pathways, we focused on changes in the cyclin-dependent kinase inhibitors and their binding partners that underlie the cell cycle arrest at senescence. As a model, we utilized normal human prostate epithelial cell (HPEC) and human uroepithelial cell (HUC) cultures. After 30-40 population doublings cells became growth-arrested in G0/1 with a threefold decrease in Cdk2-associated activity, a point defined as pre-senescence. Temporally following this growth arrest, the cells develop a senescence morphology and express senescence-associated beta-galactosidase (SA-beta-gal). Levels of p16(INK4a) and p57(KIP2) rise in HUCs during progressive passages, whereas only p16 increases in HPEC cultures. The induced expression of p57, similar to p16, produces a senescent-like phenotype. pRB, cyclin D, p19(INK4d) and p27(KIP1) decrease in both cell types. We find that p53, p21(CIP1) and p15(INK4b) are transiently elevated in HPECs and HUCs at the pre-senescent growth arrest, then return to low proliferating levels at terminal senescence. Analysis of p53, p21(CIP1), p15(INK4b), p16(INK4a), and p57(KIP2) reveals altered expression in immortalized, non-tumorigenic HPV16 E6 and E7 prostate lines and in tumorigenic prostate cancer cells. These results indicate: (i) the existence of a subset of growth inhibiting genes elevated at the onset of the senescence, (ii) a distinct class of genes involved in the maintenance of senescence, and (iii) the frequent inactivation of these pathways during immortalization.
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PMID:Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. 1178 34

The cyclin-dependent kinase inhibitor p16(INK4a) (hereafter p16) functions as a multiple tumor suppressor. Mutations in p16, which are distributed throughout the entire protein, have been identified in a variety of human cancers and cancer-derived cell lines. It is unclear how tumor-derived mutations disrupt the structure and function of p16, especially since many of these mutations are located far away from the cyclin-dependent kinase binding site. In this study, we investigated the effect of two tumor-derived mutations, P81L and V126D, on the structure of p16 by limited proteolysis. The proteolytic products were characterized by gel electrophoresis, HPLC, and mass spectrometry. Our results show that the N-terminal half of p16 is significantly more sensitive to proteolysis in both tumor-derived mutant proteins than in the wild type, suggesting that this region is particularly unstable. Interestingly, the N-terminal half of p16 contains many residues that are important for cyclin-dependent kinase binding. Thus, our results provide a structural mechanism by which tumor-derived mutations inactivate the function of p16 and suggest that stabilization of the N-terminal region could be a useful strategy for future therapeutic development.
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PMID:Structural consequences of tumor-derived mutations in p16INK4a probed by limited proteolysis. 1200 90

Trefoil factor (TFF)1 is synthesized and secreted by the normal stomach mucosa and by the gastrointestinal cells of injured tissues. The link between mouse TFF1 inactivation and the fully penetrant antropyloric tumor phenotype prompted the classification of TFF1 as a gastric tumor suppressor gene. Accordingly, altered expression, deletion, and/or mutations of the TFF1 gene are frequently observed in human gastric carcinomas. The present study was undertaken to address the nature of the cellular and molecular mechanisms targeted by TFF1 signalling. TFF1 effects were investigated in IEC18, HCT116, and AGS gastrointestinal cells treated with recombinant human TFF1, and in stably transfected HCT116 cells synthesizing constitutive or doxycycline-induced human TFF1. We observed that TFF1 triggers two types of cellular responses. On one hand, TFF1 lowers cell proliferation by delaying G1-S cell phase transition. This results from a TFF1-mediated increase in the levels of cyclin-dependent kinase inhibitors of both the INK4 and CIP subfamilies, leading to lower E2F transcriptional activity. On the other hand, TFF1 protects cells from chemical-, anchorage-free-, or Bad-induced apoptosis. In this process, TFF1 signalling targets the active form of caspase-9. Together, these results provide the first evidence of a dual antiproliferative and antiapoptotic role for TFF1. Similar paradoxical functions have been reported for tumor suppressor genes involved in cell differentiation, a function consistent with TFF1.
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PMID:The trefoil factor 1 participates in gastrointestinal cell differentiation by delaying G1-S phase transition and reducing apoptosis. 1203 70

p19(INK4d), a member of the INK4 family of cyclin-dependent kinase (CDK) inhibitors, negatively regulates the cyclin D-CDK4/6 complexes, which promote G1/S transition by phosphorylating the retinoblastoma tumor-suppressor gene product. To investigate the mechanism of transcriptional regulation of the p19(INK4d) gene, we characterized the 5'-flanking region of the human p19(INK4d) gene. The cap-site hunting method revealed that the transcription starts at -16 nucleotide (nt) upstream of the initiation codon. The 5'-flanking region of the human p19(INK4d) gene was ligated to a luciferase reporter gene and possessed functional promoter activity. Luciferase assay with a series of truncated 5'-flanking regions indicated that the region from -81 to -2 nt could drive the transcription of the p19(INK4d) gene. Several Sp1 and activating protein 2 binding sites are located within the region from -81 to -2 nt. Mutation of the second Sp1 binding site from -33 to -25 nt decreased the promoter activity. Collectively, it was demonstrated that the human p19(INK4d) gene is under the control of TATA-less promoter and the Sp1 binding site is involved in the transcription.
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PMID:Molecular cloning and characterization of the human p19(INK4d) gene promoter. 1206 51


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