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)

Proliferation, a key determinator of vascular proliferative diseases, is dependent on cyclin/cyclin-dependent kinase (CDK) complexes, which are controlled by cyclin-dependent kinase inhibitors (CKIs) such as p27(Kip1) and p21(Cip1). Both have prognostic significance in various human malignancies. We have determined the levels of p27(Kip1) and p21(Cip1) in human directional coronary atherectomy specimens of primary lesions (n = 15) and lesions of in-stent restenosis (n = 18) in comparison to those of other vascular regions and have correlated CKI levels with clinical data. Quantitative immunoblotting demonstrated low expression of p27(Kip1) in primary lesions (5.9 +/- 0.5 ng/mg protein) compared with that in aorta (14.9 +/- 0.9 ng/mg), internal mammary artery (16.7 +/- 1.1 ng/mg), and carotid artery thrombendarterectomy specimens (16.5 +/- 1.7 ng/mg). Similarly, p27(Kip1) levels in lesions of in-stent restenosis were found to be significantly reduced (6.3 +/- 1.1 ng/mg; mean time of restenosis development 367 +/- 61 days). p27(Kip1) levels did, however, not have prognostic significance for the development of restenosis, and expression levels of proliferating cell nuclear antigen and CDK2 were similar in all groups examined, indicating low proliferative activity. Clinically, p27(Kip1) was not of value in predicting the development of restenosis. Furthermore, p27(Kip1) tissue levels were not increased in statin-treated patients, implying that the favorable effect of these drugs is not a result of p27(Kip1) stabilization. However, the relative content of p21(Cip1) was found to be significantly up-regulated in restenosis compared with that in primary lesions (225%) and the other vascular regions. Our data imply that negative-feedback mechanisms are still intact in coronary proliferative disease, thereby contrasting the finding of deregulated proliferation in malignancies.
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PMID:Quantification of the cell-cycle inhibitors p27(Kip1) and p21(Cip1) in human atherectomy specimens: primary stenosis versus restenosis. 1262 99

All-trans retinoic acid (ATRA)-induced growth arrest of myeloid cells is associated with a sequential regulation of cyclins and cyclin-dependent kinase inhibitors (CKIs), which modulates the cell cycle machinery and inhibits the G1-S phase progression. ATRA treatment of myeloid cells induces up-regulation and tyrosine phosphorylation of Stat1, a member of the STAT (signal transducer and activator of transcription) transcription factor family that has been implicated in growth arrest in response to interferons. We have previously shown that ATRA-induced cell cycle arrest is dependent on tyrosinephosphorylated Stat1. In this study, we show that there is a basal level of Stat1 Ser727 phosphorylation in U-937 cells, which is transiently increased in response to ATRA treatment. Using Stat1Ser727Ala-expressing sublines, we provide evidence that Ser727 phosphorylation of Stat1 is required for ATRA-induced growth arrest. To shed further light on the role of Stat1 in ATRA-induced cell cycle arrest, cyclin and CKI expression was analyzed during ATRA treatment in U-937 sublines expressing Stat1Ser727Ala and Stat1Tyr701Phe. Our results show that Ser727/Tyr701-phosphorylated Stat1 plays a key role as a prerequisite for the ATRA-induced down-regulation of c-Myc; cyclins A, B, D2, D3, and E; and the simultaneous up-regulation of p27Kip1, associated with arrest in the G0/G1 phase of the cell cycle.
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PMID:Ser727/Tyr701-phosphorylated Stat1 is required for the regulation of c-Myc, cyclins, and p27Kip1 associated with ATRA-induced G0/G1 arrest of U-937 cells. 1263 27

The cyclin-dependent kinase inhibitor p21Cip1 has important roles in the control of cell proliferation, differentiation, senescence, and apoptosis. It has been observed that p21 is a highly unstable protein, but the mechanisms of its degradation remained unknown. We show here that p21 is a good substrate for an SCF (Skp1-Cullin1-F-box protein) ubiquitin ligase complex, which contains the F-box protein Skp2 (S phase kinase-associated protein 2) and the accessory protein Cks1 (cyclin kinase subunit 1). A similar ubiquitin ligase complex has been previously shown to be involved in the degradation of a related cyclin-dependent kinase inhibitor, p27Kip1. The levels of Skp2 oscillate in the cell cycle, reaching a maximum in S phase. The ubiquitylation of p21 in vitro required the supplementation of all components of the SCF complex as well as of Cks1 and Cdk2-cyclin E. The protein kinase Cdk2-cyclin E acts both by the phosphorylation of p21 on Ser-130 and by the formation of a complex with p21, which is required for its presentation to the ubiquitin ligase. As opposed to the case of p27, the phosphorylation of p21 stimulates its ubiquitylation but is not absolutely required for this process. Levels of p21 are higher in Skp2-/- mouse embryo fibroblasts than in wild-type fibroblasts in the S phase, and the rates of the degradation of p21 are slower in cells that lack Skp2. It is suggested that SCFSkp2 participates in the degradation of p21 in the S phase.
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PMID:Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. 1273 Jan 99

Autocrine motility factor (AMF)/phosphoglucose isomerase (PGI; EC 5.3.1.9) is a housekeeping cytosolic enzyme that plays a key role in both glycolysis and gluconeogenesis pathways. AMF/PGI is also a multifunctional protein that displays cytokine properties, eliciting mitogenic, motogenic, and differentiation activities, and has been implicated in tumor progression and metastasis. Because little is known about AMF/PGI-dependent signaling in general and during tumorigenesis in particular, we sought to study its effect on the cell cycle. To elucidate the functional role of PGI, we stably transfected its cDNA into NIH/3T3 and BALB/c 3T3-A31 fibroblasts. Ectopic overexpression of PGI results in the acquisition of a transformed phenotype associated with an acceleration of G1 to S cell cycle transition. These were manifested by up-regulation of cyclin D1 expression and cyclin-dependent kinase activity and down-regulation of the cyclin-dependent kinase inhibitor p27Kip1. The reduced p27Kip1 protein expression level in PGI-overexpressing cells could be restored to control levels by treatment with proteasome inhibitor. PGI-overexpressing cells also exhibited elevated expression of Skp2 involved in p27Kip1 ubiquitination and elevation in the levels of retinoblastoma protein hyperphosphorylation. Thus, we may conclude that the overexpression of AMF/PGI enhances cell proliferation together with up-regulation of cyclin/cyclin-dependent kinase activities and down-regulation of p27Kip1, whereas the induction of 3T3 fibroblast transformation by PGI is regulated by the retinoblastoma protein pathway.
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PMID:Regulation of cell proliferation by autocrine motility factor/phosphoglucose isomerase signaling. 1278 64

The G protein-coupled sst2 somatostatin receptor is a critical negative regulator of cell proliferation. sstII prevents growth factor-induced cell proliferation through activation of the tyrosine phosphatase SHP-1 leading to induction of the cyclin-dependent kinase inhibitor p27Kip1. Here, we investigate the signaling molecules linking sst2 to p27Kip1. In Chinese hamster ovary-DG-44 cells stably expressing sst2 (CHO/sst2), the somatostatin analogue RC-160 transiently stimulates ERK2 activity and potentiates insulin-stimulated ERK2 activity. RC-160 also stimulates ERK2 activity in pancreatic acini isolated from normal mice, which endogenously express sst2, but has no effect in pancreatic acini derived from sst2 knock-out mice. RC-160-induced p27Kip1 up-regulation and inhibition of insulin-dependent cell proliferation are both prevented by pretreatment of CHO/sst2 cells with the MEK1/2 inhibitor PD98059. In addition, using dominant negative mutants, we show that sst2-mediated ERK2 stimulation is dependent on the pertussis toxin-sensitive Gi/o protein, the tyrosine kinase Src, both small G proteins Ras and Rap1, and the MEK kinase B-Raf but is independent of Raf-1. Phosphatidylinositol 3-kinase (PI3K) and both tyrosine phosphatases, SHP-1 and SHP-2, are required upstream of Ras and Rap1. Taken together, our results identify a novel mechanism whereby a Gi/o protein-coupled receptor inhibits cell proliferation by stimulating ERK signaling via a SHP-1-SHP-2-PI3K/Ras-Rap1/B-Raf/MEK pathway.
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PMID:sst2 Somatostatin receptor inhibits cell proliferation through Ras-, Rap1-, and B-Raf-dependent ERK2 activation. 1287 7

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters B-cell differentiation, as evidenced by a marked decrease in immunoglobulin M (IgM) secretion and in the number of antibody-forming cells (AFC) induced by antigenic stimulation. The objective of the present studies was to evaluate the effect of TCDD on the level of p27kip1, a cyclin-dependent kinase inhibitor that is a critical regulator of cellular differentiation. In the well-characterized B-cell line, CH12.LX, a modest decrease in p27kip1 was observed during the initial 24-h post-LPS (lipopolysaccharide) activation, which then gradually increased above background at 48 and 72 h. Conversely, in the presence of TCDD, p27kip1 was not induced and remained unchanged from LPS unstimulated cells throughout the entire 72-h period post-LPS activation. In addition, Western blotting revealed that TCDD treatment altered the profile of p27kip1 migration as compared to the LPS-activated control. Time-of-addition studies demonstrated that the greatest sensitivity of p27kip1 to TCDD treatment occurred within the initial 24-h post-LPS activation. Interestingly, LPS-induced Ig kappa light chain and IgM secretion also exhibited the greatest period of sensitivity (i.e., inhibition) to TCDD during the first 24-h post-LPS activation. In addition, TCDD markedly suppressed the LPS-induced differentiation of CH12.LX cells into IgM secreting AFC, with a modest but cumulative effect on cell proliferation over a 72-h period. Collectively, these findings show that TCDD altered the cellular concentration and posttranslational modification of p27kip1 in this activated B-cell line model, which occurred concomitantly with altered B-cell differentiation and suggests that cyclin-dependent kinase inhibitors may be an important intracellular target in TCDD-mediated inhibition of B-cell differentiation.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the regulation and posttranslational modification of p27kip1 in lipopolysaccharide-activated B cells. 1288 80

The cyclin-dependent kinase inhibitor p27Kip1 plays an important role in cell cycle regulation. The cyclin-dependent kinase-inhibitory activity of p27Kip1 is regulated by changes in its concentration and its subcellular localization. Several reports suggest that phosphorylation of p27Kip1 at serine 10, threonine 157, and threonine 187 regulate its localization. We have previously identified that carboxyl-terminal threonine 198 (Thr198) in p27Kip1 is a novel phosphorylation site and that Akt is associated with the phosphorylation at the site (Fujita, N., Sato, S., Katayama, K., and Tsuruo, T. (2002) J. Biol. Chem. 277, 28706-28713). We show herein that activation of the Ras/Raf/mitogen-activated protein kinase kinase (MAPK kinase/MEK) pathway also regulates phosphorylation of p27Kip1 at Thr198. MAPKs were not directly associated with p27Kip1 phosphorylation at Thr198, but the p90 ribosomal protein S6 kinases (RSKs) could bind to and directly phosphorylate p27Kip1 at Thr198 in a Ras/Raf/MEK-dependent manner. RSK-dependent phosphorylation promoted the p27Kip1 binding to 14-3-3 and its cytoplasmic localization. To prove the direct relationship between 14-3-3 binding and cytoplasmic localization, we constructed a p27Kip1-R18 fusion protein in which the R18 peptide was fused to the carboxyl-terminal region of p27Kip1. The R18 peptide is known to interact with 14-3-3 independent of phosphorylation. The p27Kip1-R18 distributed mainly in the cytosol, whereas mutant p27Kip1-R18 (p27Kip1-R18-K2) that had no 14-3-3 binding capability existed mainly in the nucleus. These results indicate that RSKs play a crucial role in cell cycle progression through translocation of p27Kip1, in addition to Akt, to the cytoplasm in a phosphorylation and 14-3-3 binding-dependent manner.
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PMID:Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization. 1450 89

The cyclin-dependent kinase inhibitor p27Kip1 is frequently inactivated in human cancers. Glucocorticoids, acting through the glucocorticoid receptor (GR), are frequently used to treat certain malignancies and are growth inhibitive, but the relationship between GR activity and p27 status has not been explored. We have therefore examined GR-dependent transcriptional activation, receptor phosphorylation, and glucocorticoid-dependent growth inhibition in p27-deficient (p27-/-) murine embryonic fibroblasts (MEFs). We find that GR transcriptional enhancement as well as receptor phosphorylation at two putative cyclin-dependent kinase sites are elevated in p27-/- MEFs, relative to control cells. This increased GR transcriptional activation appears to be mediated through the GR N terminus, and coexpression of the GR N-terminal coactivator, DRIP150, further enhanced GR-dependent transcriptional activation. Furthermore, p27-/- MEFs are partially resistant to the growth inhibitory effects of glucocorticoids. Thus, p27 appears to be an important element in the GR transcription and growth inhibitory responses.
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PMID:Modulation of glucocorticoid receptor transcriptional activation, phosphorylation, and growth inhibition by p27Kip1. 1453 2

Cardiovascular diseases are the leading cause of morbidity and mortality in industrialized countries. Most cardiovascular diseases result from complications of atherosclerosis, which is a chronic and progression inflammatory condition characterized by excessive cellular proliferation of vascular smooth muscle cells, endothelial cells and inflammatory cells leading to occlusive vascular disease, myocardial infarction and stroke. Recent studies have revealed the important role of the cyclins, the cyclin-dependent kinases (CDKs), and the cyclin-dependent kinase inhibitors (CKIs) in vascular and cardiac tissue injury, inflammation and wound repair. Tissue remodeling in the cardiovascular system is a regulated balance between pro- and anti-proliferative molecules, and this balance becomes derailed in cardiovascular pathology. Understanding the circuitry of the cyclin-CDK-CKI interactions in normal physiology and disease pathology allows a better understanding of the molecular mechanisms of cardiovascular diseases and permits the rationale design of new classes of therapeutic agents for these diseases.
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PMID:The cell cycle and cardiovascular diseases. 1459 97

The cyclin-dependent kinase inhibitor p21, a major transcriptional target of the tumor suppressor p53, plays a critical role in cell cycle arrest in G1 and G2 after DNA damage. It was previously shown that in some human cell lines when S phase is arrested, p53 is transcriptionally impaired such that some p53 targets including p21 are only weakly induced. We show here that during S phase arrest proteasome-mediated turnover of p21 is significantly increased in a manner that is independent of p53. It is well established that p21 can interact both with cyclin-dependent kinase complexes and with proliferating cell nuclear antigen (PCNA). Interestingly, the scant amount of p21 detected during S phase block cannot fully saturate cyclin A-cyclin-dependent kinase 2 complexes and does not interact detectably with PCNA. Importantly, DNA elongation assays in isolated nuclei show that the C terminus of p21 containing the PCNA-binding domain effectively blocks this process. This implies that p21 down-regulation could be an essential requirement for efficient restart of DNA synthesis. In line with this, only cells expressing low levels of p21 immediately progress through the cell cycle upon release from S phase arrest, whereas the remaining few high p21 producing cells move much more slowly through S. Thus, p21 down-regulation is multiply determined and is required for the reversibility of the arrest in S phase.
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PMID:Decreased p21 levels are required for efficient restart of DNA synthesis after S phase block. 1459 17


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