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

Cyclins regulate cell cycle progression by complexing with and activating cdc2 or related kinases. PRAD1/cyclin D1 is a recently discovered putative oncogene in several types of human tumors and may regulate G1-S phase progression. We have cloned a related human cDNA, called cyclin D3, from a placental cDNA library by cross-hybridization with PRAD1. In synchronized HeLa cells, the mRNA levels of PRAD1 and cyclin D3 were regulated reciprocally through the cell cycle: cyclin D3 mRNA levels peaked in S phase, where PRAD1 mRNA was lowest in S. In normal human mammary epithelial (70N) cells synchronized by growth factor deprivation and subsequent growth factor stimulation, PRAD1 expression peaked in G1 and declined before S phase, while cyclin D3 expression rose later in G1 and remained elevated in S. Therefore, the close relationship (53.1% identity) between PRAD1 and cyclin D3 does not necessarily imply redundant functions of these candidate G1 cyclins; they may have distinct roles in progression from G1 through S phase.
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PMID:Cloning and characterization of human cyclin D3, a cDNA closely related in sequence to the PRAD1/cyclin D1 proto-oncogene. 138 1

Overexpression of c-Fos/AP-1 augments proliferation of splenic B cells stimulated with lipopolysaccharide (LPS). To elucidate mechanisms of the augmentation by c-Fos/AP-1, a cell cycle of the LPS-activated B cells from c-fos transgenic mice was analyzed. Cell cycle progression into the S phase was accelerated in the c-fos B cells. Expression of genes related to the cell cycle progression was examined in these B cells. Amount of cyclin D3 and cdk4 mRNA increased in the c-fos B cells at 6 h earlier than that in the control B cells, indicating that the kinetics of these mRNA expressions correlate with the acceleration of cell cycle progression. Furthermore, cyclin D1 and cyclin E mRNA were detected in the c-fos B cells but not in the control B cells. These results indicate that deregulated c-Fos/AP-1 modulates expression of the cyclin and the cdk gene in splenic B cells stimulated with LPS. These modulations may accelerate cell cycle progression and augment proliferation of the B cells.
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PMID:Deregulated c-Fos/AP-1 modulates expression of the cyclin and the cdk gene in splenic B cells stimulated with lipopolysaccharide. 754 12

The relationship between activation-induced growth inhibition and regulation of the cell cycle progression was investigated in T cell hybridomas by studying the function of the cell cycle-regulating genes such as G1 cyclins and their associated kinases. Activation of T cell hybridomas by anti-T cell receptor antibody induces growth arrest at G1 phase of the cell cycle and subsequently results in activation-driven cell death. Rapid reduction of both messenger RNA and protein level of the cyclin D3 is accompanied by growth arrest upon activation. Although the residual cyclin D3 protein forms a complex with cdk4 protein, cyclin D3-dependent kinase activity is severely impaired. Stable transfectants engineered to express cyclin D3 override the growth arrest upon activation. These results imply that the activation signal through T cell receptor induces the down-regulation of cyclin D3 expression and cyclin D3-dependent kinase activity, leading to growth arrest in G1 phase of the cell cycle in T cells.
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PMID:Induction of G1 arrest by down-regulation of cyclin D3 in T cell hybridomas. 762 2

L6 cells are committed skeletal muscle precursors which can be induced to differentiate into multinucleated, terminally differentiated myotubes. Upon differentiation, these immature skeletal myotubes enter a quiescent state and are unable to reenter the cell cycle. We have examined expression of a series of genes involved in regulation of progression through the G1/S boundary in undifferentiated L6 cells and during terminal differentiation of L6 myoblasts. While no change in the level of cyclin D1 transcript and a transient increase in cyclin D2 transcript were observed, a large increase in cyclin D3 expression was found. Immunohistochemistry demonstrated strong staining for cyclin D3 protein in the nuclei of the multinucleated myotubes from 4 independent myoblast cell lines; L6, L8, G8 and C2C12. Immunoprecipitation confirmed a greater than 20-fold increase in the levels of cyclin D3 protein in the differentiated L6 myotubes as well as its association with a number of proteins. Western assays demonstrated, further, that cyclin D3 was complexed with the cyclin dependent-kinases, cdk2 and cdk4, in differentiated L6 cells. However, while kinase activity specific for a GST-pRB fusion protein was seen for cyclin D3-containing complexes isolated from undifferentiated cells, the high levels of cyclin D3 in the differentiated myotubes had no associated kinase activity. These data demonstrate that cyclin D3 may also have a function in terminally differentiated, quiescent cells. The lack of cyclin D3-associated kinase activity and its association with a number of different proteins suggest that cyclin D3 may regulate the function of other proteins by direct interaction with these factors.
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PMID:Expression of the positive regulator of cell cycle progression, cyclin D3, is induced during differentiation of myoblasts into quiescent myotubes. 782 68

While testing purines related to the non-specific protein kinase inhibitors N6-dimethylaminopurine and N6-(delta 2-isopentenyl)adenine as potential inhibitors of the p34cdc2/cyclin B kinase, we discovered a compound with high specificity, 2-(2-hydroxyethylamino)-6- benzylamino-9-methylpurine (olomoucine). Kinetic analysis of kinase inhibition reveals that olomoucine behaves as a competitive inhibitor for ATP and as a non-competitive inhibitor for histone H1 (linear inhibition for both substrates). The kinase specificity of this inhibition was investigated for 35 highly purified kinases (including p34cdk4/cyclin D1, p40cdk6/cyclin D3, cAMP-dependent and cGMP-dependent kinases, eight protein kinase C isoforms, calmodulin-dependent kinase II, myosin light-chain kinase, mitogen-activated S6 kinase, casein kinase 2, double-stranded RNA-activated protein kinase, AMP-stimulated kinase, eight tyrosine kinases). Most kinases are not significantly inhibited. Only the cell-cycle regulating p34cdc2/cyclin B, p33cdk2/cyclin A and p33cdk2/cyclin E kinases, the brain p33cdk5/p35 kinase and the ERK1/MAP-kinase (and its starfish homologue p44mpk) are substantially inhibited by olomoucine (IC50 values are 7, 7, 7, 3 and 25 microM, respectively). The cdk4/cyclin D1 and cdk6/cyclin D3 kinases are not significantly sensitive to olomoucine (IC50 values greater than 1 mM and 150 microM, respectively). N6-(delta 2-Isopentenyl)adenine is confirmed as a general kinase inhibitor with IC50 values of 50-100 microM for many kinases. The purine specificity of cyclin-dependent kinase inhibition was investigated: among 81 purine derivatives tested, only C2, N6 and N9-substituted purines exert a strong inhibitory effect on the p34cdc2/cyclin B kinase. An essentially similar sensitivity to this olomoucine family of compounds was observed for the brain-specific cdk5/p35 kinase. Structure/activity relationship studies allow speculation on the interactions of olomoucine and its analogues with the kinase catalytic subunit. Olomoucine inhibits in vitro M-phase-promoting factor activity in metaphase-arrested Xenopus egg extracts, inhibits in vitro DNA synthesis in Xenopus interphase egg extracts and inhibits the licensing factor, an essential replication factor ensuring that DNA is replicated only once in each cell cycle. Olomoucine inhibits the starfish oocyte G2/M transition in vivo. Through its unique selectivity olomoucine provides an anti-mitotic reagent that may preferentially inhibit certain steps of the cell cycle.
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PMID:Inhibition of cyclin-dependent kinases by purine analogues. 792 96

Differentiation of murine erythroleukemia cells induced by hexamethylene bisacetamide (HMBA) is associated with accumulation of underphosphorylated retinoblastoma protein (pRB) and an increase in retinoblastoma (RB) gene expression. Here we show that HMBA causes a rapid decrease in the level of cyclin-dependent kinase 4 (cdk4) protein. This decrease results from decreased stability of the protein, while the rate of synthesis of the protein is not affected by HMBA. The decrease in the level of cdk4 protein is followed by suppression of the pRB kinase activity associated with cdk4. Cyclin D3, which can bind and activated cdk4, is increased in HMBA-induced cells and is found in complex with pRB and the transcription factor E2F. In uninduced cells cyclin D3 complexes with pRB and E2F are barely detected. At the later stages of differentiation, MEL cells become arrested in G1 and cdk2 kinase activity is suppressed; this is accompanied by a decrease in the level of cyclin A and cdk2 proteins. Cells transfected with cdk4, which continue to overexpress cdk4 protein during culture with HMBA, are resistant to HMBA-induced differentiation. In contrast, overexpression of cdk2 protein does not inhibit induced differentiation. These findings suggest that suppression of cdk4 is a critical event in the pathway leading to terminal differentiation of erythroleukemia cells.
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PMID:Suppression of cyclin-dependent kinase 4 during induced differentiation of erythroleukemia cells. 793 34

We used targeted homologous recombination to disrupt one c-myc gene copy in a diploid fibroblast cell line and found that a twofold reduction in Myc expression resulted in lower exponential growth rates and a lengthening of the G0-to-S-phase transition (M. Shichiri, K. D. Hanson and J. M. Sedivy, Cell Growth Differ. 4:93-104, 1993). Myc is a transcription factor, and the number of target genes whose regulation could result in differential growth rates may be very large. We have approached this problem by examining effects of reduced c-myc expression in three broad areas: (i) secretion of growth factors, (ii) expression of growth factor receptors, and (iii) intracellular signal transduction between Myc and components of the intrinsic cell cycle clock. We have found no evidence that differential medium conditioning can account for the growth phenotypes. Likewise, the expression of receptors for platelet-derived growth factor, epidermal growth factor, basic fibroblast growth factor, and insulin-like growth factor I was the same in diploid and heterozygous cells (platelet-derived growth factor, epidermal growth factor, fibroblast growth factor, and insulin-like growth factor are the sole growth factors required by these cells for growth in serum-free medium). In contrast, expression of cyclin E, cyclin A, and Rb phosphorylation were delayed when quiescent c-myc heterozygous cells were stimulated to enter the cell cycle. Expression of cyclin D1, cyclin D3, and Cdk2 was not affected. The timing of cyclin E induction was the earliest observable effect of reduced Myc expression. Our data indicate that Myc contributes to regulation of proliferation by a cell-autonomous mechanism that involves the modulation of cyclin E expression and, consequently, progression through the restriction point of the cell cycle.
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PMID:Effects of c-myc expression on cell cycle progression. 806 9

D-type cyclin-dependent kinase activities have not so far been detected in mammalian cells. Lysis of rodent fibroblasts, mouse macrophages, or myeloid cells with Tween 20 followed by precipitation with antibodies to cyclins D1, D2, and D3 or to their major catalytic partner, cyclin-dependent kinase 4 (cdk4), yielded kinase activities in immune complexes which readily phosphorylated the retinoblastoma protein (pRb) but not histone H1 or casein. Virtually all cyclin D1-dependent kinase activity in proliferating macrophages and fibroblasts could be attributed to cdk4. When quiescent cells were stimulated by growth factors to enter the cell cycle, cyclin D1-dependent kinase activity was first detected in mid G1, reached a maximum near the G1/S transition, and remained elevated in proliferating cells. The rate of appearance of kinase activity during G1 phase lagged significantly behind cyclin induction and correlated with the more delayed accumulation of cdk4 and formation of cyclin D1-cdk4 complexes. Thus, cyclin D1-associated kinase activity was not detected during the G0-to-G1 transition, which occurs within the first few hours following growth factor stimulation. Rodent fibroblasts engineered to constitutively overexpress either cyclin D1 alone or cyclin D3 together with cdk4 exhibited greatly elevated cyclin D-dependent kinase activity, which remained absent in quiescent cells but rose to supraphysiologic levels as cells progressed through G1. Therefore, despite continued enforced overproduction of cyclins and cdk4, the assembly of cyclin D-cdk4 complexes and the appearance of their kinase activities remained dependent upon serum stimulation, indicating that upstream regulators must govern formation of the active enzymes.
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PMID:D-type cyclin-dependent kinase activity in mammalian cells. 811 38

Differentiation of skeletal myoblasts into contractile myotubes is associated with permanent withdrawal from the cell cycle. Little is known about the expression of cell cycle regulating genes during terminal differentiation of muscle cells. We investigated the expression pattern, biological activity, and cellular localization of cyclins and cyclin-dependent kinases during terminal differentiation of the mouse skeletal myogenic cell line C2C12. After induction of differentiation by serum deprivation, cdc2 mRNA levels transiently increased, followed by a down-regulation to undetectable levels within 42 h. In contrast, cdk2 mRNA stayed constant during this period. During differentiation cyclin A, B, and C were down-regulated within 24 h to undetectable levels. Interestingly, cyclin D1/CYL1 mRNA was up-regulated by twofold at 9-12 h after serum deprivation followed by a down-regulation to undetectable levels within 42 h, while cyclin D3/CYL3 mRNA levels remained constant. Restimulation of the differentiated myotube culture with serum reinduced cdc2 as well as cyclin D1/CYL1 mRNA close to the levels observed in dividing myoblasts. At the protein level p34cdc2 was detected in nuclei of proliferating myoblasts and nascent myotubes, but not in mature myotubes. Restimulation with serum-induced p34cdc2 protein in a small minority of unfused myoblasts, but never in myotubes. Histone H1 kinase activity of p34cdc2 decreased during differentiation while p33cdk2 activity did not change. These findings suggest that terminal differentiation of skeletal muscle cells is associated with a differential regulation of cyclins and their associated kinases. Inability to accumulate p34cdc2 protein in response to serum stimulation, despite the induction of its mRNA, in differentiated myotubes may play an important role in maintaining the postmitotic state of skeletal muscle in the presence of high concentrations of growth factors.
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PMID:Cyclins and cyclin-dependent kinases are differentially regulated during terminal differentiation of C2C12 muscle cells. 818 22

D-type cyclins are necessary and rate-limiting for G1 progression during the mammalian cell cycle. Cyclins D1, D2, and D3 are encoded by distinct genes and are expressed in proliferating cells in a lineage-specific manner. Monoclonal antibodies (mAbs) generated to bacterially produced recombinant D-type cyclins were able to react with the native proteins expressed in mammalian cells. One mouse and three rat mAbs immunoprecipitated cyclin D1 from mouse macrophages. Only rat mAbs reacted with human cyclin D1 and cross-reacted with cyclin D2 expressed in proliferating T lymphocytes and human tumor cell lines. A single rat mAb to cyclin D2 exhibited a pattern of reactivity reciprocal to that of rat mAbs to D1. Three rat mAbs reacted specifically with mouse or human cyclin D3, but did not cross-react with cyclins D1 or D2 from either species. Representative mAbs were useful for immunoblotting and detected D-type cyclins coprecipitating in complexes recovered with antiserum to cyclin-dependent kinase-4 (CDK4). Because these mAbs detect D-type cyclins in the nuclei of fixed permeabilized cells, they should prove useful in documenting cyclin overexpression in those human tumors in which the genes are amplified or are targets of specific chromosomal rearrangements.
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PMID:Monoclonal antibodies to mammalian D-type G1 cyclins. 820 Jun 57


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