Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

EBV-immortalized lymphoblastoid B cell lines (LCLs) are a suitable in vitro model for the study of EBV-related lymphoproliferative disorders of immunosuppressed patients. We have previously shown that 9-cis-, 13-cis- and all-trans-retinoic acid (RA) powerfully inhibit LCL proliferation at concentrations corresponding to therapeutically achievable plasma levels (10(-6) M). Herein we show that RA-induced LCL accumulation in the G0/G1 phases correlated with the loss of the catalytic activity of all three G1-associated CDKs (CDK2, CDK4 and CDK6) and with increased levels of underphosphorylated pRb and, in some LCLs, p130. LCLs arrested in G0/G1 by RA also showed a significant decrease in the protein levels of cyclins D2, D3 and A, together with a reduction in the amount of cyclin D associated with CDK4 and CDK6, probably accounting for the inhibition of the relative kinase activity. In addition, RA-treated LCLs showed a marked up-regulation of the CDK inhibitor (CKI) p27Kip-1 at the protein but not mRNA level, which correlated with a progressive increase of p27Kip-1 in CDK2 complexes (more than 2.5-fold) and with a reduction in the active phosphorylated form of CDK2. p27Kip-1 may also contribute to the inhibition of CDK4 kinase activity, as the amount of CDK4-associated p27Kip-1 was increased by 50% after RA exposure. p27Kip-1 up-regulation stably persisted for more than one week after RA withdrawal concomitantly with the maintenance of the proliferative block. Moreover, neutralization of TGFbeta did not affect the growth inhibitory activity of RA, suggesting that LCL growth arrest induced by these retinoids is probably not mediated by a pathway directly involving TGFbeta. Overall, these results demonstrate that RA treatment of EBV-immortalized B lymphocytes is associated with multiple effects on G1 regulatory proteins, including p27Kip1 up-regulation, decreased levels of cyclins D2, D3 and A, and inhibition of CDK2, CDK4 and CDK6 activity, which ultimately result in reduced pRb phosphorylation and G0/G1 growth arrest.
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PMID:Retinoic acid-mediated growth arrest of EBV-immortalized B lymphocytes is associated with multiple changes in G1 regulatory proteins: p27Kip1 up-regulation is a relevant early event. 977 49

Angiotensin II has been shown to be mitogenic in various cell types. In cultured neonatal cardiomyocytes, we have demonstrated that angiotensin II causes hypertrophy, not hyperplasia. However, fetal or neonatal cardiomyocytes exhibit limited proliferation in primary culture, and are mitotically less potent. In order to determine whether angiotensin II is simply a hypertrophic or hyperplastic growth factor for mitotically-potent cardiomyocytes, we analysed [3H]-thymidine uptake and cell cycle-regulated gene expression using SV40 large T-transformed AT-1 cardiomyocytes. Angiotensin II, alone and in combination with other growth factors, increased [3H]-thymidine uptake in a dose-dependent manner. The mRNA expression of G1 cyclins (Cyclin C, D1, D2, D3) and histone H1-kinase activity by CDK2 increased 6 h after angiotensin II stimulation. Western blot analysis revealed cyclin B1 expression after 18 h , which peaked at 30 h. Histone H1-kinase activity by cdc2 was also increased by angiotensin II, and peaked at 24-36 h, indicating that these changes were cell cycle dependent. Double immunofluorescent photography showed that AT-1 cells incorporated BrdU, and expressed cdc2 by angiotensin II stimulation. [3H]-thymidine and BrdU uptake were blocked by losartan, but not by PD123319. In contrast with neonatal cardiomyocytes, angiotensin II potentiated DNA synthesis and induced cell cycle regulated gene expression in AT-1 cardiomyocytes, and this activity was mediated by the angiotensin II type-1 receptor.
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PMID:Angiotensin II potentiates DNA synthesis in AT-1 transformed cardiomyocytes. 979 60

The role of cell cycle dependent molecules in controlling the switch from cardiac myocyte hyperplasia to hypertrophy remains unclear, although in the rat this process occurs between day 3 and 4 after birth. In this study we have determined (1) cell cycle profiles by fluorescence activated cell sorting (FACS); and (2) expressions, co-expressions and activities of a number of cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors by reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting and in vitro kinase assays in freshly isolated rat cardiac myocytes obtained from 2, 3, 4 and 5-day-old animals. The percentage of myocytes found in the S phase of the cell cycle decreased significantly during the transition from hyperplasia to hypertrophy (5.5, 3.5, 2.3 and 1.9% of cells in 2-, 3-, 4- and 5-day-old myocytes, respectively,P<0.05), concomitant with a significant increase in the percentage of G0/G1 phase cells. At the molecular level, the expressions and activities of G1/S and G2/M phase acting cyclins and CDKs were downregulated significantly during the transition from hyperplasia to hypertrophy, whereas the expressions and activities of G1 phase acting cyclins and CDKs were upregulated significantly during this transition. In addition, p21(CIP1)- and p27(KIP1)- associated CDK kinase activities remained relatively constant when histone H1 was used as a substrate, whereas phosphorylation of the retinoblastoma protein was upregulated significantly during the transition from hyperplasia to hypertrophy. Thus, there is a progressive and significant G0/G1 phase blockade during the transition from myocyte hyperplasia to hypertrophy. Whilst CDK2 and cdc2 may be pivotal in the withdrawal of cardiac myocytes from the cell cycle, CDK4 and CDK6 may be critical for maintaining hypertrophic growth of the myocyte during development.
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PMID:Expressions and activities of cell cycle regulatory molecules during the transition from myocyte hyperplasia to hypertrophy. 1160 19

Exposure of CV-1P cells to hypoxic conditions results in reversible cell cycle arrest concomitant with accumulation of pRB in the hypophosphorylated, growth suppressive form. Similar to cell cycle arrest induced by serum starvation, we show here that hypoxia-induced arrest is accompanied by a decrease in pRB-directed CDK4 and CDK2 activities, lower cyclin D and E protein levels, and by an increase in p27 protein abundance. Immunoprecipitation studies reveal an increase in p27 association with cyclin E-CDK2 complexes. In contrast to cell cycle arrest induced by serum starvation, hypoxia increases PP1-mediated pRB dephosphorylation. These data reveal that synergy between decreased pRB-directed cyclin/CDK activity and increased pRB-directed phosphatase activity contribute towards inducing and maintaining pRB in its hypophosphorylated, growth suppressive state during hypoxia.
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PMID:Hypoxia-induced pRB hypophosphorylation results from downregulation of CDK and upregulation of PP1 activities. 981 60

G1 cyclin E controls the initiation of DNA synthesis by activating CDK2, and abnormally high levels of cyclin E expression have frequently been observed in human cancers. We have isolated a novel human cyclin, cyclin E2, that contains significant homology to cyclin E. Cyclin E2 specifically interacts with CDK inhibitors of the CIP/KIP family and activates both CDK2 and CDK3. The expression of cyclin E2 mRNA oscillates periodically throughout the cell cycle, peaking at the G1/S transition, and exhibits a pattern of tissue specificity distinct from that of cyclin E1. Cyclin E2 encodes a short lived protein whose turnover is most likely governed by the proteasome pathway and is regulated by phosphorylation on a conserved Thr-392 residue. Expression of the viral E6 oncoprotein in normal human fibroblasts increases the steady state level of cyclin E2, but not cyclin E1, while expression of the E7 oncoprotein upregulates both. These data suggest that the expression of these two G1 E-type cyclins may be similarly regulated by the pRb function, but distinctly by the p53 activity.
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PMID:Cyclin E2, a novel human G1 cyclin and activating partner of CDK2 and CDK3, is induced by viral oncoproteins. 984 Sep 43

Cell cycle control by cdc2-related kinases (CRKs) is essential to the regulation of cell proliferation and developmental processes in many organisms. Alternating phases of growth, arrest, and differentiation are characteristics of the infectious cycle of many trypanosomatid parasites, raising the possibility that members of the trypanosomatid CRK gene family participate in the regulation of these essential processes. Here we describe properties of the CRK3 gene from Leishmania major, which encodes a 36 kDa protein kinase showing 60% amino acid sequence identity with human CDK2, including several conserved sites implicated in regulation of kinase activity. CRK3 mRNA was constitutively expressed throughout the parasite life cycle, but histone H1 kinase activity of an epitope tagged CRK3 protein was greater in log-phase than in stationary-phase promastigotes. When integrated into the genome and expressed at the optimal level, CRK3 was able to rescue the growth defect of a Schizosaccharomyces pombe cdc2 mutant (cdc2-33(ts)), indicating that CRK3 is a functional homolog of cdc2. Mutants of CRK3 at several key regulatory residues showed the expected dominant negative effects on the S. pombe mutant. This is the first example of functional expression of a trypanosomatid CRK in yeast, opening the way for further genetic studies within this amenable organism.
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PMID:Stage-specific activity of the Leishmania major CRK3 kinase and functional rescue of a Schizosaccharomyces pombe cdc2 mutant. 985 13

Permanent withdrawal of skeletal myoblasts from the cell cycle precedes differentiation. We examined the changes of protein levels of cell cycle regulators and the activities of CDKs in differentiating (by serum deprivation) or in differentiation-inhibited (by serum deprivation + TGF-beta1 treated) C2C12 skeletal myocytes. Regardless of differentiation, protein levels of most cyclins declined over time while this effect was delayed slightly by TGF-beta1 for cyclins D1 and F. Although the protein levels of CDKs gradually decreased over time, the activities of CDK2 and cdc2 decreased dramatically between 0 and 12 h after serum deprivation in both groups. Decreased CDK2 and cdc2 activities were temporally related to decreased DNA synthesis. While the p27KIP1 protein increased in both groups, the p21CIP1 protein increased only in differentiating cells. In vivo, protein expressions of cyclins, CDKs, and p21CIP1 were high in fetal, but almost undetectable in adult skeletal muscle. In contrast, the levels of p27KIP1 protein in skeletal muscle were high throughout development. Thus, changes of cell cycle regulators in differentiating C2C12 myocytes paralleled those during skeletal muscle development of mice. These results suggest that the rapid reduction of DNA synthesis and activities of CDKs slow reduction of protein levels of cyclins and CDKs, and that the increase of p27KIP1 are programmed mechanisms upon mitogen deprivation regardless of differentiation in skeletal myocytes.
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PMID:Programmed changes of cell cycle regulators by serum deprivation regardless of skeletal myocyte differentiation. 985 54

Cell cycle progression is dependent on the sequential activity of cyclin-dependent kinases (CDKs). For full activity, CDKs require an activating phosphorylation of a conserved residue (corresponding to Thr160 in human CDK2) carried out by the CDK-activating kinase (CAK). Two distinct CAK kinases have been described: in budding yeast Saccharomyces cerevisiae, the Cak1/Civ1 kinase is responsible for CAK activity. In several other species including human, Xenopus, Drosophila and fission yeast Schizosaccharomyces pombe, CAK has been identified as a complex homologous to CDK7-cyclin H (Mcs6-Mcs2 in fission yeast). Here we identify the fission yeast Csk1 kinase as an in vivo activating kinase of the Mcs6-Mcs2 CAK defining Csk1 as a CAK-activating kinase (CAKAK).
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PMID:Fission yeast Csk1 is a CAK-activating kinase (CAKAK). 985 80

In hematopoietic cells, gamma-irradiation causes a p53-dependent transient G1 phase cell cycle arrest. Various extracellular growth inhibitory signals elicit G1 arrest by targeting CDK4. Here we show that in a myeloid cell line, 32D cl 3, enforced expression of CDK4, but not cyclins D2 nor D3, overrides the gamma-irradiation-induced G1 arrest. CDK4 does not confer resistance to the radiation-induced G2 block observed in parental cells. Ectopic expression of CDK4 overcomes the ionizing radiation-induced inhibition of CDK4 and CDK2 kinase activity. The levels of CDK4 protein do not change after exposure to ionizing radiation in either parental cells or those overexpressing CDK4. Ionizing radiation induces the expression of both p53 and p21, and in cells constitutively synthesizing exogenous CDK4, the return of p53 protein levels to baseline is prolonged. Increased levels of p21 are found associated with CDK4, and not CDK2, in the lines overexpressing CDK4, compared to the parental line, after exposure to ionizing radiation. Enforced expression of CDK4 may therefore overcome a gamma-irradiation-induced G1 arrest through the titration of the CDK inhibitor p21 allowing both CDK4 and CDK2 to remain active.
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PMID:Enforced CDK4 expression in a hematopoietic cell line confers resistance to the G1 arrest induced by ionizing radiation. 988 98

Varicella-zoster virus (VZV) glycoprotein gI is a type 1 transmembrane glycoprotein which is one component of the heterodimeric gE:gI Fc receptor complex. Like VZV gE, VZV gI was phosphorylated in both VZV-infected cells and gI-transfected cells. Preliminary studies demonstrated that a serine 343-proline 344 sequence located within the gI cytoplasmic tail was the most likely phosphorylation site. To determine which protein kinase catalyzed the gI phosphorylation event, we constructed a fusion protein, consisting of glutathione-S-transferase (GST) and the gI cytoplasmic tail, called GST-gI-wt. When this fusion protein was used as a substrate for gI phosphorylation in vitro, the results demonstrated that GST-gI-wt fusion protein was phosphorylated by a representative cyclin-dependent kinase (CDK) called P-TEFb, a homologue of CDK1 (cdc2). When serine 343 within the serine-proline phosphorylation site was replaced with an alanine residue, the level of phosphorylation of the gI fusion protein was greatly reduced. Subsequent experiments with individually immunoprecipitated mammalian CDKs revealed that the VZV gI fusion protein was phosphorylated best by CDK1, to a lesser degree by CDK2, and not at all by CDK6. Transient-transfection assays carried out in the presence of the specific CDK inhibitor roscovitine strongly supported the prior results by demonstrating a marked decrease in gI phosphorylation while gI protein expression was unaffected. Finally, the possibility that VZV gI contained a CDK phosphorylation site in its endodomain was of further interest because its partner, gE, contains a casein kinase II phosphorylation site in its endodomain; prior studies have established that CDK1 can phosphorylate casein kinase II.
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PMID:Varicella-zoster virus Fc receptor component gI is phosphorylated on its endodomain by a cyclin-dependent kinase. 988 37


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