Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:029451 (cyclin-dependent kinase 2)
 882 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human cyclin E, originally identified on the basis of its ability to function as a G1 cyclin in budding yeast, associated with a cell cycle-regulated protein kinase in human cells. The cyclin E-associated kinase activity peaked during G1, before the appearance of cyclin A, and was diminished during exit from the cell cycle after differentiation or serum withdrawal. The major cyclin E-associated kinase in human cells was Cdk2 (cyclin-dependent kinase 2). The abundance of the cyclin E protein and the cyclin E-Cdk2 complex was maximal in G1 cells. These results provide further evidence that in all eukaryotes assembly of a cyclin-Cdk complex is an important step in the biochemical pathway that controls cell proliferation during G1.
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PMID:Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. 138 88

Changes in the levels of cyclins A, D, and E, p21, and cyclin-dependent kinase 2 (CDK2) were examined in rat pheochromocytoma PC12 cells during neuronal differentiation induced by nerve growth factor (NGF). Expression of cyclin A decreased to an undetectable level after 5 days of exposure to NGF, while expression of CDK2 decreased gradually after day 3. In contrast, the levels of cyclins D1 and E increased gradually through day 10, yet the amount of cyclin E associated with CDK2 decreased concomitant with a decrease in the CDK2 protein level. p21 expression increased gradually after day 7, while the level of CDK2-associated p21 remained unchanged. When human cDNAs encoding cyclins and CDK2 were introduced into PC12 cells, only CDK2 overexpression inhibited NGF-induced differentiation. The cell lines overexpressing CDK2 showed stable and high levels of CDK2 kinase activity during differentiation, whereas parental and vector-transfected cell lines displayed a marked decline in CDK2 kinase activity 1 day after NGF treatment. In cell lines overexpressing cyclins A, D, and E, this reduction of the kinase activity was not apparent until day 3. These results suggest that down-regulation of CDK2 activity is a crucial event for the neuronal differentiation of PC12 cells.
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PMID:Constitutive overexpression of CDK2 inhibits neuronal differentiation of rat pheochromocytoma PC12 cells. 755 42

Staurosporine (ST), a protein kinase inhibitor, at a concentration of 20 nM arrests normal diploid fibroblasts 3 h into G1 (H. A. Crissman et al., Proc. Natl. Acad. Sci. USA, 88: 7580-7584, 1991; K. Abe et al., Exp. Cell Res., 192: 122-127, 1991). ST (2 nM) induces a new G1 arrest point at 6 h into G1. Partial phosphorylation of the retinoblastoma protein was observed at the 2 nM ST arrest point, whereas the retinoblastoma protein was unphosphorylated or underphosphorylated at the 20 nM arrest point. This correlated with the activity of the cyclin-dependent kinase 2 (CDK2) and the phosphorylation of the Thr160 residue of p33CDK2. The cyclin E and cyclin D1/2 levels were reduced at the 20 nM ST arrest point. In HeLa cells that do not arrest in G1 in response to 2 or 20 nM ST, the retinoblastoma protein and CDK2 phosphorylations and CDK2 activity were not affected by ST. These results suggest that ST inhibits one or more G1-regulating protein kinases, which lie upstream of CDK2.
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PMID:The kinase inhibitor staurosporine induces G1 arrest at two points: effect on retinoblastoma protein phosphorylation and cyclin-dependent kinase 2 in normal and transformed cells. 795 29

We isolated two types of hamster cyclin-dependent kinase 2 (cdk2) cDNAs from BHK21 cells derived from Golden hamsters. One type of cdk2 (cdk2hm) encodes the 32 kDa protein consisting of 298 predicted amino acids and shows strong homology to the cdk2 cDNAs of humans and Xenopus. The other cdk2 (cdk2Lhm) encodes the 38 kDa protein containing the insertion of 48 amino acids in the cdk2hm protein. Immunoblotting analysis suggested that these two types of cdk2 protein exist in mammalian cells. The cdk2hm has the activity of protein kinase, while the cdk2Lhm does not, however, both bind with cyclin E.
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PMID:Molecular cloning and identification of two types of hamster cyclin-dependent kinases: cdk2 and cdk2L. 828 Jan 71

Recent evidence has suggested that human cyclin-dependent kinase 2 (CDK2) is an essential regulator of cell cycle progression through S phase. CDK2 is known to complex with at least two distinct human cyclins, E and A. The kinase activity of these complexes peaks in G1 and S phase, respectively. The vertebrate CDC2/cyclin B1 complex is an essential regulator of the onset of mitosis and is inhibited by phosphorylation of CDC2 on Thr-14 and Tyr-15. In vitro, CDC2/cyclin B1 is activated by treatment with the members of the Cdc25 family of phosphatases. We found that, like CDC2, CDK2 is also phosphorylated on Thr-14 and Tyr-15 and that treatment of cyclin A or cyclin E immunoprecipitates with bacterially expressed Cdc25M2 (the mouse homolog of human CDC25B) increased the histone H1 kinase activity of these immune complexes 5- to 10-fold. Tryptic peptide mapping demonstrated that Cdc25M2 treatment of cyclin A or cyclin B1 immune complexes resulted in the specific dephosphorylation of Thr-14 and Tyr-15 on CDK2 or CDC2, respectively. Thus, we have confirmed that Cdc25 family members comprise a class of dual-specificity phosphatases. Furthermore, our data suggest that the phosphorylation and dephosphorylation of CDKs on Thr-14 and Tyr-15 may regulate not only the G2/M transition but also other transitions in the cell cycle and that individual cdc25 family members may regulate distinct cell cycle checkpoints.
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PMID:Cdc25M2 activation of cyclin-dependent kinases by dephosphorylation of threonine-14 and tyrosine-15. 847 1

Transforming growth factor-beta1 (TGF-beta1) is a potent inhibitor of hematopoietic cell growth. Here we report that TGF-beta1 signals inhibition of IL-3-dependent 32D-123 murine myeloid cell growth by modulating the activities of cyclin E and cyclin-dependent kinase 2 (cdk2) proteins and their complex formation in the G1 phase of the cell cycle. Whereas the cyclin E protein was hyperphosphorylated in TGF-beta1 treated cells, TGF-beta1 decreased both the phosphorylation of cdk2 and the kinase activity of the cyclin E-cdk2 complex. Decreased cyclin E-cdk2 kinase activity correlated with decreased phosphorylation of the retinoblastoma-related protein p107. In support of these observations, transient overexpression of p107 inhibited the proliferation of the myeloid cells, and expression of antisense oligodeoxynucleotides to p107 mRNA blocked TGF-beta1 inhibition of myeloid cell growth. Furthermore, as reported previously, in 32D-123 TGF-beta1 treated cells, c-Myc protein expression was decreased. TGF-beta1 increased the binding of p107 to the transcription factor E2F, leading to decreased c-Myc protein levels. p107 inhibited E2F transactivation activity and was also found to bind the c-Myc protein, suggesting p107 negative regulation of c-Myc protein function. These studies demonstrate the modulation of p107 function by TGF-beta1 and suggest a novel mechanism by which TGF-beta1 blocks cell cycle progression in myeloid cells.
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PMID:Transforming growth factor-beta1 modulates p107 function in myeloid cells: correlation with cell cycle progression. 863 25

Rat fibroblasts transformed by a temperature-sensitive mutant of murine p53 undergo a reversible growth arrest in G1 at 32.5 degrees C, the temperature at which p53 adopts a wild-type conformation. The arrested cells contain inactive cyclin-dependent kinase 2 (cdk2) despite the presence of high levels of cyclin E and cdk-activating kinase activity. This is due in part to p53-dependent expression of the p2l cdk inhibitor. Upon shift to 39 degrees C, wild-type p53 is lost and cdk2 activation and pRb phosphorylation occur concomitantly with loss of p2l. This p53-mediated growth arrest can be abrogated by overexpression of cdk4 and cdk6 but not cdk2 or cyclins, leading to continuous proliferation of transfected cells in the presence of wild-type p53 and p2l. Kinase-inactive counterparts of cdk4 and cdk6 also rescue these cells from growth arrest, implicating a noncatalytic role for cdk4 and cdk6 in this resistance to p53-mediated growth arrest. Aberrant expression of these cell cycle kinases may thus result in an oncogenic interference with inhibitors of cell cycle progression.
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PMID:Inhibition of p53-mediated growth arrest by overexpression of cyclin-dependent kinases. 875 45

Proteases are known to play important roles in cell growth control, although the underlying mechanisms are still poorly understood. Here we show that the protease inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal induced cell cycle arrest in platelet-derived growth factor-stimulated human fibroblasts at the G1/S boundary of the cell cycle by inhibiting the proteasome. Inhibition of the proteasome resulted in accumulation of the tumor suppressor p53, which was followed by an increase in the amount of the cyclin-dependent kinase-inhibitor p21. As a consequence, both phosphorylation and activity of the cyclin-dependent kinase 2/cyclin E complex were inhibited. We further observed that the retinoblastoma gene product, pRb, remained in the hypophosphorylated state, thus preventing cells from progression into the S-phase. These studies strongly support the hypothesis that the proteasome is a key regulator in the G1-phase of cell cycle progression.
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PMID:p53-dependent cell cycle arrest induced by N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal in platelet-derived growth factor-stimulated human fibroblasts. 885 63

Fibroblasts derived from embryos homozygous for a disruption of the retinoblastoma gene (Rb) exhibit a shorter G1 than their wild-type counterparts, apparently due to highly elevated levels of cyclin E protein and deregulated cyclin-dependent kinase 2 (CDK2) activity. Here we demonstrate that the Rb-/- fibroblasts display higher levels of phosphorylated H1 throughout G1 with the maximum being 10-fold higher than that of the Rb+/+ fibroblasts. This profile of intracellular H1 phosphorylation corresponds with deregulated CDK2 activity observed in in vitro assays, suggesting that CDK2 may be directly responsible for the in vivo phosphorylation of H1. H1 phosphorylation has been proposed to lead to a relaxation of chromatin structure due to a decreased affinity of this protein for chromatin after phosphorylation. In accord with this, chromatin from the Rb-/- cells is more susceptible to micrococcal nuclease digestion than that from Rb+/+ fibroblasts. Increased H1 phosphorylation and relaxed chromatin structure have also been observed in cells expressing several oncogenes, suggesting a common mechanism in oncogene and tumor suppressor gene function.
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PMID:Increased histone H1 phosphorylation and relaxed chromatin structure in Rb-deficient fibroblasts. 887 66

The experiments described in this report were undertaken to define the parameters that regulate cyclin E/cyclin-dependent kinase 2 (Cdk2) kinase activity in mitotically quiescent, serum-starved fibroblastic cells and in cells that had been stimulated to enter the cell cycle and progress through G1 into S phase. We have analyzed the expression of cyclin E and Cdk2, the extent to which these two proteins form complexes, and the enzymatic activity of cyclin E/cdk2 kinase. Particular attention was focused upon subcellular localization and the effect of compartmentalization on the association between cyclin E and Cdk2. In addition, we have examined the interaction of cyclin E/Cdk2 complexes with two well-characterized inhibitors of Cdk2 kinase activity, Cip1 and Kip1. This represents the first report in which all of these parameters have been measured simultaneously in a single, normal diploid cell line. In G0 cells, there is abundant cyclin E and Cdk2, yet there is little or no detectable Cdk2-dependent histone H1 kinase activity. After serum stimulation, there is a rapid increase in the amount of cyclin E that is bound to Cdk2, although there is no significant change in the abundance of either the cyclin or the Cdk. Immunocytochemical data indicate that cyclin E, Cip1, and Kip1 are located within the nuclei of cell in G0, but very little Cdk2 is observed within the nuclei of serum-starved cells. Cdk2 rapidly enters the nucleus upon serum stimulation. The abundance of the cyclin E/Cdk2 complex increases to the extent that the binding capacity of Cip1 is exceeded about 8-12 h after serum stimulation. The abundance of Kip1 decreases at the same time that the Cip1 threshold is exceeded, so that cyclin E/Kip1-containing complexes decrease by 90% within 8-12 h. Cyclin E/Cdk2 kinase activity begins to increase rapidly thereafter, reaching a maximum level about 16 h after serum stimulation. We have been unable to detect histone H1 kinase activity in complexes that contain cyclin E bound to Kip1 or Cip1. We conclude that compartmentalization is the predominant barrier to activation of cyclin E-dependent kinases in quiescent cells. Cip1 and Kip1 serve to prevent premature activation of cyclin E/Cdk2 complexes that form during G0 or early G1.
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PMID:Cyclin E/Cdk2 activity is controlled by different mechanisms in the G0 and G1 phases of the cell cycle. 889 32


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