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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

INH, a type 2A protein phosphatase (PP2A), negatively regulates entry into M phase and the cyclin B-dependent activation of cdc2 in Xenopus extracts. INH appears to be central to the mechanism of the trigger for mitotic initiation, as it prevents the premature activation of cdc2. We first show that INH is a conventional form of PP2A with a B alpha regulatory subunit. We next explore the mechanism by which it inhibits cdc2 activation by examining the effect of purified PP2A on the reaction pathways controlling cdc2 activity. Our results suggest that although PP2A inhibits the switch in tyrosine kinase and tyrosine phosphatase activities accompanying mitosis, this switch is a consequence of the inhibition of some other rate-limiting event. In the preactivation phase, PP2A inhibits the pathway leading to T161 phosphorylation, suggesting that this activity may be one of the rate-limiting events for transition. However, our results also suggest that the accumulation of active cdc2/cyclin complexes during the lag is only one of the events required for triggering entry into mitosis.
Mol Biol Cell 1994 Mar
PMID:Inhibition of cdc2 activation by INH/PP2A. 804 24

The insulin-like growth factors (IGFs) stimulate cell division by modulating events occurring during the prereplicative (G1) phase of the cell cycle, but identification of the critical events has proved difficult. Recent observations suggest that progression through the cell cycle is dependent on the activation of a group of serine-threonine-specific protein kinases whose activities are regulated by accessory proteins, termed cyclins. The identification of cyclin species expressed during G1 has led to the hypothesis that modulation of cyclin expression may be the critical event regulated by growth factors. The present studies were undertaken to determine whether the IGFs regulate the expression of specific G1 cyclins in MG63, a human cell line that is unusually responsive to IGF, and to characterize this effect. We found that in these cells IGF-I stimulates the cyclin-dependent kinases, and that stimulation is associated with an increase in cyclin-D1 mRNA and protein expression. The increase in cyclin-D1 occurs early in G1 and corresponds to the portion of the cell cycle in which IGF acts on these cells. The increase in cyclin-D1 mRNA is due at least in part to an increase in the rate of transcription initiation of the gene. The mRNA levels of cyclin-B1 (a G2 cyclin) and two cyclin-dependent kinases, cdc2 and cdk2, also increased in response to IGF, but at later times. These results are consistent with the hypothesis that IGF modulation of D-type cyclin expression plays a role in the regulation of cell replication.
Mol Endocrinol 1994 Apr
PMID:Insulin-like growth factor-I induces cyclin-D1 expression in MG63 human osteosarcoma cells in vitro. 805 69

The change of proliferative activity in mouse kidney cortex cells due to aging was studied by PCNA/cyclin immunostaining. Mouse kidney tissues of various ages: late fetal, newborn, suckling, weaning, adult and senescent were used for this experiment. Small pieces of kidney tissues were fixed in methacarn solution and embedded in paraffin. Sections were stained with PCNA/cyclin monoclonal antibody. The reaction product for PCNA/cyclin was observed mainly on nuclei. The ratio of the PCNA/cyclin positive nuclei to the total number of nuclei were calculated. PCNA/cyclin positive ratios in glomeruli and uriniferous tubules in the superficial layer were higher than those in the deep layer from late fetal period to suckling period. They decreased due to aging after birth and became to nearly zero after weaning period.
Cell Mol Biol (Noisy-le-grand) 1993 Mar
PMID:Proliferative activity in the kidneys of aging mice evaluated by PCNA/cyclin immunohistochemistry. 809 38

Conditional overexpression of human cyclins B1, D1, and E was accomplished by using a synthetic cDNA expression system based on the Escherichia coli tetracycline repressor. After induction of these cyclins in asynchronous Rat-1 fibroblasts, a decrease in the length of the G1 interval was observed for cyclins D1 and E, consistent with an acceleration of the G1/S phase transition. We observed, in addition, a compensatory lengthening of S phase and G2 so that the mean cell cycle length in populations constitutively expressing these cyclins was unchanged relative to those of their uninduced counterparts. We found that expression of cyclin B1 had no effect on cell cycle dynamics, despite elevated levels of cyclin B-associated histone H1 kinase activity. Induction of cyclins D1 and E also accelerated entry into S phase for synchronized cultures emerging from quiescence. However, whereas cyclin E exerted a greater effect than cyclin D1 in asynchronous cycling cells, cyclin D1 conferred a greater effect upon stimulation from quiescence, suggesting a specific role for cyclin D1 in the G0-to-G1 transition. Overexpression of cyclins did not prevent cells from entering into quiescence upon serum starvation, although a slight delay in attainment of quiescence was observed for cells expressing either cyclin D1 or cyclin E. These results suggest that cyclins D1 and E are rate-limiting activators of the G1-to-S phase transition and that cyclin D1 might play a specialized role in facilitating emergence from quiescence.
Mol Cell Biol 1994 Mar
PMID:Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. 811 3

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.
Mol Cell Biol 1994 Mar
PMID:D-type cyclin-dependent kinase activity in mammalian cells. 811 38

The gene encoding a 40-kDa protein, previously studied as a substrate and inhibitor of the yeast cyclin-dependent protein kinase, Cdc28, has been cloned. The DNA sequence reveals that p40 is a highly charged protein of 32,187 Da with no significant homology to other proteins. Overexpression of the gene encoding p40, SIC1, produces cells with an elongated but morphology similar to that of cells with depleted levels of the CLB gene products, suggesting that p40 acts as an inhibitor of Cdc28-Clb complexes in vivo. A SIC1 deletion is viable and has highly increased frequencies of broken and lost chromosomes. The deletion strain segregates out many dead cells that are primarily arrested at the G2 checkpoint in an asymmetric fashion. Only daughters and young mothers display the lethal defect, while experienced mothers appear to grow normally. These results suggest that negative regulation of Cdc28 protein kinase activity by p40 is important for faithful segregation of chromosomes to daughter cells.
Mol Cell Biol 1994 May
PMID:An inhibitor of yeast cyclin-dependent protein kinase plays an important role in ensuring the genomic integrity of daughter cells. 816 83

Transforming growth factor beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Cyclins E and A in association with Cdk2 have been shown to play a role in the G1-to-S phase transition in mammalian cells. We have studied the effects of TGF-beta-mediated growth arrest on G1/S cyclins E and A. Inhibition of cyclin A-associated kinase by TGF-beta is primarily due to a decrease in cyclin A mRNA and protein. By contrast, while TGF-beta inhibits accumulation of cyclin E mRNA, the reduction in cyclin E protein is minimal. Instead, we find that the activation of cyclin E-associated kinase that normally accompanies the G1-to-S phase transition is inhibited. A novel inhibitor of cyclin-Cdk complexes was detected in TGF-beta-treated cell lysates. Inhibition is mediated by a heat-stable protein that targets both Cdk2 and Cdc2 kinases. In G0-arrested cells, a similar inhibitor of Cdk2 kinase was detected. These data suggest the existence of an inhibitor of cyclin-dependent kinases induced under different conditions to mediate antiproliferative responses.
Mol Cell Biol 1994 Jun
PMID:A novel inhibitor of cyclin-Cdk activity detected in transforming growth factor beta-arrested epithelial cells. 819 12

The identification of numerous cyclin-dependent kinases (cdk) and G1 cyclins suggests that cell cycle progression through G1/S may be controlled in a tissue-specific manner by various cdk/cyclin complexes. In situ hybridization was used to characterize expression of the cyclin-dependent kinase cdk4 in prenatal and postnatal rat lung and other tissues and to determine whether cdk4 expression is limited to proliferating cells, identified by BrdU incorporation and cdk1 mRNA expression. cdk4 co-localized with cdk1 in proliferating cells of both prenatal and postnatal lung and other tissues, consistent with an SPF function that is not tissue-specific. The distribution of cdk1 and cdk4 expression was identical in fetal rat tissues and was detected in lung parenchyma and throughout the airway. Pulmonary cell proliferation declined with increasing postnatal age and could be found only in focal areas of day 21 terminal and respiratory bronchiolar epithelium. Proliferation was undetectable in adult lung. Postnatal cdk4 expression was not restricted to cells expressing cdk1: cdk4 was evenly distributed in bronchiolar epithelium and was present throughout the airway and alveolar septae of day 21 lung. Expression of cdk4 was also maintained in adult bronchiolar epithelium. These studies demonstrate that although the expression of cdk1 is tightly correlated with proliferative capacity, the expression of cdk4 is not limited to proliferating cells, suggesting that cdk4 may have additional cell-specific functions unrelated to cell cycle progression.
Am J Respir Cell Mol Biol 1993 Nov
PMID:Expression of the cyclin-dependent kinase cdk4 in perinatal and adult rat lung. 821 95

Kin28 is an essential serine-threonine kinase of Saccharomyces cerevisiae. Multicopies of a novel cyclin gene, CCL1, are able to suppress the thermosensitivity of two kin28-ts mutants. The CCL1 gene is not cyclically transcribed, yet its product is also essential for cell proliferation. Furthermore, when overexpressed under high expression promoter, Cell is able to replace G1 function of Cln cyclins. Cell and Kin28 are physically associated in vivo. Therefore, like p34CDC28/cdc2, Kin28 may be a cyclin dependent kinase which is required for cell proliferation.
J Mol Biol 1993 Nov 20
PMID:The kin28 protein kinase is associated with a cyclin in Saccharomyces cerevisiae. 823 Feb 16

The beta and gamma subunits of the mating response G-protein in the yeast Saccharomyces cerevisiae have been shown to transmit the mating pheromone signal to downstream components of the pheromone response pathway. A protein kinase homologue encoded by the STE20 gene has recently been identified as a potential G beta gamma target. We have searched multicopy plasmid genomic DNA libraries for high gene dosage suppressors of the signal transduction defect of ste20 mutant cells. This screen identified the STE5 gene encoding an essential component of the pheromone signal transduction pathway. We provide genetic evidence for a functional interrelationship between the STE5 gene product and the Ste20 protein kinase. We have sequenced the STE5 gene, which encodes a predicted protein of 917 amino acids and is specifically transcribed in haploid cells. Transcription is slightly induced by treatment of cells with pheromone. Ste5 has homology with Far1, a yeast protein required for efficient mating and the pheromone-inducible inhibition of a G1 cyclin, Cln2. A STE5 multicopy plasmid is able to suppress the signal transduction defect of far1 null mutant cells suggesting that Ste5, at elevated levels, is able functionally to replace Far1. The genetically predicted point of function of Ste5 within the pheromone signalling pathway suggests that Ste5 is involved in the regulation of a G beta gamma-activated protein kinase cascade which links a G-protein coupled receptor to yeast homologues of mitogen-activated protein kinases.
Mol Gen Genet 1993 Nov
PMID:Cloning of Saccharomyces cerevisiae STE5 as a suppressor of a Ste20 protein kinase mutant: structural and functional similarity of Ste5 to Far1. 824 77


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