Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

During corneal epithelial wound repair, cells migrating to cover the wound area exhibit a drastic reduction in proliferative activity. In contrast, cells distal to the original wound exhibit a greatly enhanced level of proliferative activity. At least 90% of the basal cells in limbal and peripheral corneal epithelia synchronously progress through the cell cycle. The question addressed in this article is whether cyclin-dependent kinase inhibitors play a role in the alterations in proliferative activity seen during corneal wound repair. These inhibitors specifically block cells in the G1-phase of the cell cycle. Two families of cyclin-dependent kinase inhibitors have been identified. The CIP/KIP family includes p21, p27, and p57, while the INK4 family consists of p16. p15. p18. and pI9. At least five of these inhibitors are present in the corneal epithelium. The expression of two of these, p15 and p27. is dramatically altered during wound repair, suggesting that they may be involved in the changes in cell proliferation observed during corneal wound healing.
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PMID:Expression of cyclin-dependent kinase inhibitors during corneal wound repair. 1074 77

Functional defects in the CIP/KIP family of cyclin-dependent kinase inhibitors (CDKIs) have been shown to be associated with human malignancies. We immunohistochemically examined p57KIP2 (p57) expression in 92 patients with human esophageal squamous cell carcinoma (SCC) to determine the relationship between this expression and those of cyclin D1 and E. The p57 labeling index (LI) (defined as the percentage of p57-positive cells) in esophageal SCC was 43.3 +/- 3.2% (mean +/- standard error of the mean). In non-neoplastic esophageal epithelium, p57 staining was more frequently observed in the basal and parabasal cells than in surface layer cells. Immunostaining for cyclin D1 and E was observed in 28.2% (28/92) and 32.6% (30/92) of tumors, respectively. The median p57 LI in cyclin D1-positive cases was 66.2, and significantly higher than that in negative cases (31.9%) (p = 0.0009). There was no significant relationship between p57 LI and cyclin E expression (p = 0.147). As determined using Kaplan-Meier's method, loss of p57 immunoreactivity was not a prognostic factor for esophageal SCC (p = 0.548). Our in vivo findings suggested that p57 protein expression was positively correlated with cyclin D1 expression and that loss of p57 protein expression alone does not affect progression of esophageal SCC.
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PMID:Immunohistochemical characterization of p57KIP2 expression in human esophageal squamous cell carcinoma. 1092 32

The present study was designed to determine the spatial correlation among extent of DNA synthetic activity, expressions of G(1)/S phase cyclins, cyclin-dependent kinases (CDKs) and CIP/KIP family of CDK inhibitors (CKIs), and activities of G(1)/S phase CDKs in glomeruli and outer medullae of kidneys during the active regeneration period after ischemic injury. DNA synthetic activity was measured using [(3)H]-thymidine autoradiogram in the kidney sections. Cyclin, CDK, and CKI proteins were determined by Western blot analysis. CDK activities were determined by phosphorylation amount using specific substrate. The protein levels of cyclins (D1, D3, E, A) and activities of CDK4 and CDK2 were increased concomitant with the induction of DNA synthetic activity in outer medullae, but not in glomeruli, in adult kidneys during DNA synthetic period after ischemic injury. The p27(KIP1) protein, but not the p21(CIP1) protein, increased equally in total kidney, glomeruli, and outer medullae after ischemic injury. These results indicate that renal tubules have an active cyclin/CDK system, while glomeruli, do not have a cyclin/CDK system during active regeneration of kidneys after ischemic injury.
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PMID:Differential changes of CDK activities in glomeruli and tubules during the active DNA synthetic period after ischemic injury. 1109 88

From an expression screen in a fish model, the medaka, we have isolated Ol-KIP (Oryzias latipes-kinase inhibitor protein), a new member of the KIP subfamily of cyclin-dependent kinase (Cdk) inhibitors. We have analysed its expression in the developing and adult brain by in situ hybridization and by double labeling with Ol-KIP mRNA and proliferating cell nuclear antigen (PCNA) antibodies. Ol-KIP presents a complex expression pattern in several areas of the embryonic central nervous system, most often in close vicinity to proliferative neuroepithelia. We studied in great detail its expression in the optic tectum: Ol-KIP is expressed in a ring-shaped domain lying exactly between the proliferative and the postmitotic zones of this structure and is, therefore, potentially involved in cell cycle exit. In the adult CNS, Ol-KIP expression persists in numerous nuclei, both close and distant from proliferative ventricular areas. So, Ol-KIP expression is in part compatible with a sustained "stop signal" role for proliferation, but its expression in postmitotic zones suggests that KIP proteins may have late neuronal function(s), in addition to inhibiting Cdks. This first detailed study of the expression profile of a KIP gene in a nonmammalian vertebrate, thus, opens perspectives for analysing the role of these regulators in brain development and function.
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PMID:Expression of Ol-KIP, a cyclin-dependent kinase inhibitor, in embryonic and adult medaka (Oryzias latipes) central nervous system. 1174 78

Generation of distinct cell types and numbers in developing cerebral cortex is subject to regulation by extracellular factors that positively or negatively control precursor proliferation. Although signals stimulating proliferation are well described, factors halting cell cycle progression are less well defined. At the molecular level, production and association of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CKIs) regulate cycle progression. We now report that the endogenous peptide, pituitary adenylate cyclase activating polypeptide (PACAP), negatively regulates the cell cycle by inhibiting p57Kip2-dependent CDK2 activity in embryonic cortex. Protein levels of CDK2 and members of the CIP/KIP family of CKIs (p27Kip1, p57Kip2) were detected in developing rat cortex from embryonic day 13.5 through postnatal day 2. With advancing development, CDK2 protein levels decreased, whereas CKI expression increased, suggesting that stimulatory and inhibitory cycle proteins control cell cycle exit. Using a well defined, nonsynchronized, 8 hr precursor culture, PACAP decreased the fraction of cells crossing the G1/S boundary, inhibiting DNA synthesis by 35%. CDK2 kinase activity was inhibited 75% by PACAP, whereas kinase protein and its regulatory cyclin E subunit were unaffected. Moreover, decreased kinase activity was accompanied by a twofold increase in levels of p57Kip2 protein, but not p21Cip1 or p27Kip1, suggesting that p57Kip2 mediates PACAP anti-mitogenic effects. Indeed, immunoprecipitation of CDK2 complex revealed increased p57Kip2 association with the kinase and concomitant reduction in free inhibitor after PACAP exposure, suggesting that p57Kip2 interactions directly regulate CDK2 activity. These observations establish a mechanism whereby anti-mitogenic signals actively induce cell cycle withdrawal in developing cortex.
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PMID:Pituitary adenylate cyclase activating polypeptide anti-mitogenic signaling in cerebral cortical progenitors is regulated by p57Kip2-dependent CDK2 activity. 1188 Apr 88

The p21 is a downstream effector of p53/p73 and belongs to the CIP/KIP family of cyclin-dependent kinase inhibitors (CDKIs). It is, therefore, a potential tumor suppressor gene and probably plays an important role in tumor development. Moreover, reduced expression of p21 has been reported to have prognostic value in several human malignancies. In contrast with other CDKIs, mutational inactivation of p21 is infrequent, but gene inactivation by an alternative mechanism seems to be the general pathway. In this study, we analyzed the methylation status of the p21 promoter region using semiquantitative polymerase chain reaction in 124 patients with acute lymphoblastic leukemia (ALL). We observed p21 hypermethylation in bone marrow cells from 41% (51 of 124) of ALL patients. Hypermethylation within promoter strongly correlated with decreased p21 messenger RNA expression in tumoral cells. Clinical, molecular, and laboratory features and complete remission rate did not differ significantly between hypermethylated and normally methylated patients. Estimated disease-free survival (DFS) and overall survival at 7 and 9 years, respectively, were 59% and 65% for healthy patients and 6% and 8% for hypermethylated patients (P =.00001 and P =.006). Multivariate analysis of potential prognostic factors demonstrated that p21 methylation status was an independent prognostic factor in predicting DFS (P =.0001). Our results indicate that the p21 gene is subject to methylation regulation at the transcription level in ALL and seems to be an important factor in predicting the clinical outcome of these patients.
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PMID:5' CpG island hypermethylation is associated with transcriptional silencing of the p21(CIP1/WAF1/SDI1) gene and confers poor prognosis in acute lymphoblastic leukemia. 1241 76

In all eukaryotes, cell cycle progression is controlled by cyclin-dependent kinases (CDKs) whose activity is regulated at several levels including inhibition by CDK inhibitors. Here, we report a comparative molecular and functional analysis of the tobacco (Nicotiana tomentosiformis) CDK inhibitor, NtKIS1a, and its spliced variant, NtKIS1b. The C-terminal end of NtKIS1a shares strong sequence similarity with mammalian CIP/KIP inhibitors, which is not the case for NtKIS1b. Consistent with this, NtKIS1a but not NtKIS1b inhibits in vitro the kinase activity of CDK/cyclin complexes, and tobacco (Nicotiana tabacum) D-type cyclins and an A-type CDK are NtKIS1a, but not NtKIS1b, interacting partners. Although both NtKIS1a and NtKIS1b transcripts are mainly found in flowers and more precisely in stamens, NtKIS1b transcript levels are cell cycle regulated, whereas those of NtKIS1a remain constant during the cell cycle. NtKIS1a and NtKIS1b fused to fluorescent proteins are localized in the nucleus when transiently expressed in onion epidermal cells. Furthermore, there is no competition for their nuclear localization when they are simultaneously overexpressed. In vitro competition toward CDK kinase activity suggests that NtKIS1b is a strong competitor of NtKIS1a. Arabidopsis plants overexpressing NtKIS1a-green fluorescent protein (GFP) or NtKIS1b-GFP fusion proteins were obtained. In these plants, the fusion proteins are still localized in the nucleus. Interestingly, NtKIS1a-GFP-overexpressing plants display strong morphological modifications and a reduced CDK kinase activity, whereas NtKIS1b-GFP-overexpressing plants display a wild-type phenotype including a wild-type CDK kinase activity. Our results strongly suggest that the inhibition of the kinase activity is responsible for the phenotypic modifications.
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PMID:Comparative molecular and functional analyses of the tobacco cyclin-dependent kinase inhibitor NtKIS1a and its spliced variant NtKIS1b. 1248 Oct 70

Productive infection and replication of herpesviruses usually occurs in growth-arrested cells, but there has been no direct evidence in the case of Epstein-Barr virus (EBV), since an efficient lytic replication system without external stimuli does not exist for the virus. Expression of the EBV lytic-switch transactivator BZLF1 protein in EBV-negative epithelial tumor cell lines, however, is known to arrest the cell cycle in G(0)/G(1) by induction of the tumor suppressor protein p53 and the cyclin-dependent kinase (CDK) inhibitors p21(WAF-1/CIP-1) and p27(KIP-1), followed by the accumulation of a hypophosphorylated form of the Rb protein. In order to determine the effect of the onset of lytic viral replication on cellular events in latently EBV-infected B LCLs, a tightly controlled induction system of the EBV lytic-replication program by inducible BZLF1 protein expression was established in B95-8 cells. The induction of lytic replication completely arrested cell cycle progression and cellular DNA replication. Surprisingly, the levels of p53, p21(WAF-1/CIP-1), and p27(KIP-1) were constant before and after induction of the lytic program, indicating that the cell cycle arrest induced by the lytic program is not mediated through p53 and the CDK inhibitors. Furthermore, although cellular DNA replication was blocked, elevation of cyclin E/A expression and accumulation of hyperphosphorylated forms of Rb protein were observed, a post-G(1)/S phase characteristic of cells. Thus, while the EBV lytic program promoted specific cell cycle-associated activities involved in the progression from G(1) to S phase, it inhibited cellular DNA synthesis. Such cellular conditions appear to especially favor viral lytic replication.
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PMID:Reactivation of lytic replication from B cells latently infected with Epstein-Barr virus occurs with high S-phase cyclin-dependent kinase activity while inhibiting cellular DNA replication. 1250 1

Immunohistochemistry was performed for p21, p27, p57 and p53 on paraffin-embedded tissue sections from 25 patients who had surgically resected intestinal lymphomas. It was then correlated with the patients' clinical course in an attempt to determine the expression patterns and clinical significance of the CIP/KIP family of cyclin-dependent kinase inhibitors in primary intestinal large B-cell lymphomas. p21 immunostaining was positive in 11 cases (44%) and p27 was positive in 8 cases (32%). All cases were p57-negative. p53 immunostaining was positive in 14 cases (56%) and negative in 11 cases (44%). With respect to the relationship between p21 and p53, seven cases were p53+/p21-, seven cases were p53+/p21+, seven cases were p53-/p2l-, and four cases were p53-/p21+. The expression patterns of p21 and p53 did not influence the patient's clinical outcome. However, p27-positive cases had a much higher percentage of patients sustaining a continuous complete remission state (8/8, 100%) as compared to p27-negative cases (10/17, 59%), although this difference was not statistically significant (p = 0.057). These results suggest that p27 immunoreactivity may be associated with a better clinical outcome. However, further study with larger series are planned to determine the clinical significance of p27 overexpression in primary intestinal large B-cell lymphomas.
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PMID:Expressions of the CIP/KIP family of CDK inhibitor proteins in primary intestinal large B-cell lymphomas: correlation with clinical outcomes. 1253 May 77

Pulsed-field gradient (PFG) diffusion NMR spectroscopy studies were conducted with several helix-loop-helix regulatory Ca(2+)-binding proteins to characterize the conformational changes associated with Ca(2+)-saturation and/or binding targets. The calmodulin (CaM) system was used as a basis for evaluation, with similar hydrodynamic radii (R(h)) obtained for apo- and Ca(2+)-CaM, consistent with previously reported R(h) data. In addition, conformational changes associated with CaM binding to target peptides from myosin light chain kinase (MLCK), phosphodiesterase (PDE), and simian immunodeficiency virus (SIV) were accurately determined compared with small-angle X-ray scattering results. Both sets of data demonstrate the well-established collapse of the extended Ca(2+)-CaM molecule into a globular complex upon peptide binding. The R(h) of CaM complexes with target peptides from CaM-dependent protein kinase I (CaMKI) and an N-terminal portion of the SIV peptide (SIV-N), as well as the anticancer drug cisplatin were also determined. The CaMKI complex demonstrates a collapse analogous to that observed for MLCK, PDE, and SIV, while the SIV-N shows only a partial collapse. Interestingly, the covalent CaM-cisplatin complex shows a near complete collapse, not expected from previous studies. The method was extended to related calcium binding proteins to show that the R(h) of calcium and integrin binding protein (CIB), calbrain, and the calcium-binding region from soybean calcium-dependent protein kinase (CDPK) decrease on Ca(2+)-binding to various extents. Heteronuclear NMR spectroscopy suggests that for CIB and calbrain this is likely because of shifting the equilibrium from unfolded to folded conformations, with calbrain forming a dimer structure. These results demonstrate the utility of PFG-diffusion NMR to rapidly and accurately screen for molecular size changes on protein-ligand and protein-protein interactions for this class of proteins.
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PMID:Protein conformational changes studied by diffusion NMR spectroscopy: application to helix-loop-helix calcium binding proteins. 1253 86


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