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)

The Raf family of protein kinases display differences in their abilities to promote the entry of quiescent NIH 3T3 cells into the S phase of the cell cycle. Although conditional activation of deltaA-Raf:ER promoted cell cycle progression, activation of deltaRaf-1:ER and deltaB-Raf:ER elicited a G1 arrest that was not overcome by exogenously added growth factors. Activation of all three deltaRaf:ER kinases led to elevated expression of cyclin D1 and cyclin E and reduced expression of p27Kip1. However, activation of deltaB-Raf:ER and deltaRaf-1:ER induced the expression of p21Cip1, whereas activation of deltaA-Raf:ER did not. A catalytically potentiated form of deltaA-Raf:ER, generated by point mutation, strongly induced p21Cip1 expression and elicited cell cycle arrest similarly to deltaB-Raf:ER and deltaRaf-1:ER. These data suggested that the strength and duration of signaling by Raf kinases might influence the biological outcome of activation of this pathway. By titration of deltaB-Raf:ER activity we demonstrated that low levels of Raf activity led to activation of cyclin D1-cdk4 and cyclin E-cdk2 complexes and to cell cycle progression whereas higher Raf activity elicited cell cycle arrest correlating with p21Cip1 induction and inhibition of cyclin-cdk activity. Using green fluorescent protein-tagged forms of deltaRaf-1:ER in primary mouse embryo fibroblasts (MEFs) we demonstrated that p21Cip1 was induced by Raf in a p53-independent manner, leading to cell cycle arrest. By contrast, activation of Raf in p21Cip1(-/-) MEFs led to a robust mitogenic response that was similar to that observed in response to platelet-derived growth factor. These data indicate that, depending on the level of kinase activity, Raf can elicit either cell cycle progression or cell cycle arrest in mouse fibroblasts. The ability of Raf to elicit cell cycle arrest is strongly associated with its ability to induce the expression of the cyclin-dependent kinase inhibitor p21Cip1 in a manner that bears analogy to alpha-factor arrest in Saccharomyces cerevisiae. These data are consistent with a role for Raf kinases in both proliferation and differentiation of mammalian cells.
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PMID:Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. 927 35

Cell adhesion to substratum is essential for the transition of G1 to S phase in mouse BALB/c 3T3 fibroblast cell cycle. Loss of cell adhesion in late G1 phase caused blockage of the G1/S phase transition and repression of cyclin E-associated cyclin-dependent kinase-2 (CDK2) activity. A CDK2 inhibitor abundant in quiescent cells, p27Kip1, was down-regulated by growth factors in serum, and this down-regulation was partially prevented by loss of cell adhesion. Another CDK2 inhibitor, p21Cip1/WAF1, which was undetectable in quiescent cells, was markedly induced by loss of cell adhesion. In exponentially growing cells, loss of cell adhesion also induced p21Cip1/WAF1 expression but did not affect the abundance of p27Kip1. These results suggest that loss of cell adhesion to substratum up-regulates p21Cip1/WAF1 expression, which plays an essential role for arresting the BALB/c 3T3 fibroblast cell cycle.
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PMID:Loss of cell adhesion to substratum up-regulates p21Cip1/WAF1 expression in BALB/c 3T3 fibroblasts. 929 73

We have characterized the expression and activity of the cell cycle regulatory machinery and the organization of the cytoskeleton of the p16(Ink4a)-deficient astrocytoma cell line, U343 MG-a (U343), following retinoic acid (RA) treatment. RA causes cell cycle arrest at low cell density and significant morphological changes in U343 cells, reflected by reorganization of the intermediate filament, GFAP, and actin. RA-induced cell cycle arrest is also associated with induction of p27Kip1 expression, inhibition of cdk2-associated kinase activity and alteration of the phosphorylation state of the pRB-family proteins. We next determined the effect of inducing expression of the cyclin dependent kinase inhibitors (CKI's), p16(Ink4a), p21Cip1/Waf1 or p27Kip1 on the proliferation and morphology of these malignant astrocytoma cells in the absence and presence of RA. Induction of p16, p21 or p27, using the tetracycline repressor system, potently inhibits proliferation of U343 cells. However, rather than resembling RA-treated cells, CKI-induced U343 cells become flat with abundant cytoplasm and perinuclear vacuolization. CKI-induced morphological alterations are accompanied by a significant reorganization of glial filaments within the cytoplasm. Interestingly, when U343 cells are growth arrested by p16, p21 or p27 induction and treated simultaneously with RA, a dramatic morphological change occurs, cells acquiring multiple long, tapering processes reminiscent of primary astrocytes. This rearrangement is accompanied by reorganization of GFAP, vimentin and actin. Vimentin specifically relocalizes to the tips of the long processes which form. The arrangement of intermediate filaments in these cells is, in fact, indistinguishable from their arrangement in primary human astrocytes. These data demonstrate that when a strong proliferative block, produced by CKI expression, occurs in conjunction with the morphogenic signals generated by RA, these p16-deficient malignant astrocytoma cells are induced to phenotypically resemble normal astrocytes.
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PMID:Retinoic acid and the cyclin dependent kinase inhibitors synergistically alter proliferation and morphology of U343 astrocytoma cells. 936 21

The passage of mammalian cells through the restriction point into the S phase of the cell cycle is regulated by the activities of Cdk4 and Cdk6 complexed with the D-type cyclins and by cyclin E/Cdk2. The activities of these holoenzymes are constrained by CDK inhibitory proteins. The importance of the restriction point is illustrated by its deregulation in many tumour cells and upon infection with DNA tumour viruses. Here we describe the properties of cyclins encoded by two herpesviruses, herpesvirus saimiri (HVS) which can transform blood lymphocytes and induce malignancies of lymphoid origin in New World primates, and human herpesvirus 8 (HHV8) implicated as a causative agent of Kaposi's sarcoma and body cavity lymphomas. Both viral cyclins form active kinase complexes with Cdk6 that are resistant to inhibition by the CDK inhibitors p16(Ink4a), p21Cip1 and p27Kip1. Furthermore, ectopic expression of a viral cyclin prevents G1 arrest imposed by each inhibitor and stimulates cell-cycle progression in quiescent fibroblasts. These results suggest a new mechanism for deregulation of the cell cycle and indicate that the viral cyclins may contribute to the oncogenic nature of these viruses.
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PMID:Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins. 936 57

The cell cycle events accompanying TGF-beta1-induced growth arrest of normal mouse resting B lymphocytes stimulated by LPS were investigated. We showed that TGF-beta1 prevents the retinoblastoma protein (pRb) phosphorylation and induces growth arrest in mid- to late G1. To explore the molecular basis of the effect of TGF-beta1, we analyzed the in vitro kinase activities of cyclin/cyclin-dependent kinase (cdk) complexes involved in the progression through G1 phase and in the G1/S transition, by using the glutathione S-transferase-pRb fusion protein as a substrate. Cdk2-associated kinase activity was strongly induced in mitogen-treated B cells. It was dramatically inhibited by TGF-beta1 as were the cyclin E- and cyclin A-dependent kinase activities. TGF-beta1 treatment had no significant effect on the expression of two G1/S phase proteins, cyclin E and cdk2. In contrast, the appearance of cyclin A, occuring in late G1 phase, was almost totally inhibited by TGF-beta1. We also showed that expression of the cdk inhibitor protein p27Kip1 decreased as cells progressed through the G1 phase. An accumulation of p27 was found in TGF-beta1-treated cells, showing that TGF-beta1 prevented LPS-induced decline of p27. Finally we found that the lack of kinase activity associated with cyclin E/cdk2 complexes was correlated with increased amounts of cdk2- and cyclin E-bound p27. Overall, these results suggest that both cyclin A and cdk2 may be active participants in the TGF-beta1-induced cell cycle arrest in normal mouse B cells and indicate the involvement of p27 in this mechanism.
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PMID:Effect of TGF-beta1 on cell cycle regulatory proteins in LPS-stimulated normal mouse B lymphocytes. 937 8

Myxoid and round cell liposarcoma represents a morphological spectrum in which tumor progression from low-grade myxoid to high-grade round cell areas is frequently observed. A distinctive t(12;16)(q13;p11) reciprocal translocation rearranges the CHOP gene localized to 12q13 in most cases. Data concerning the occurrence of cell cycle aberrations in this subset of mesenchymal malignancies are very limited. Therefore, we analyzed a histologically homogeneous series of 21 cases of myxoid and round cell liposarcoma. The p53 pathway was studied by investigating the TP53 gene and protein, mdm2 protein, and p21Waf1 protein. The Rb-cyclin D pathway was analyzed by studying the pRb protein, the p16MTS1 gene, cyclin D1, cyclin D3, p27Kip1, cdk4, and cdk6 proteins. In contrast with the rare involvement of the TP53 gene in well differentiated liposarcoma, aberrations of the TP53 gene were observed in approximately 30% of cases of myxoid and round cell liposarcoma. Notably, mdm2 overexpression was seen in 56% of cases and correlated with histological grade, therefore indicating a possible role in tumor progression. Abnormalities involving the Rb-cyclin D pathway were observed in more than 90% of cases. pRb loss was present in one-third of cases and, at variance with that observed in other subsets of sarcoma, overexpression of cyclin Ds represented a rare event. Interestingly, upregulation of either cdk4 or cdk6 was demonstrated in 85% of cases.
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PMID:Molecular aberrations of the G1-S checkpoint in myxoid and round cell liposarcoma. 940 3

An immunosuppressant Rapamycin (Rap) has been reported to cause G1 arrest by inhibiting p70 S6 kinase and G1 cyclin/cdks kinase activities when added to quiescent cells with mitogens. However, antiproliferative effects of Rap on exponentially growing cells have been poorly investigated. We examined the intracellular events after the treatment of Rap in exponentially growing T cells and found that Rap upregulated a cdks inhibitor, p27Kip1 at both mRNA and protein levels in Rap-sensitive cells. Antiproliferative effect of Rap was mainly ascribed to the inhibition of cyclin E/cdk2 kinase activity through the formation of cyclin E/cdk2-p27Kip1 complex rather than inhibition of p70 S6 kinase activity. Furthermore, we showed that Rap-sensitive cells with elevated p27Kip1 expression lost sensitivity to Rap when antisense p27Kip1 was introduced, which indicates that the basal level of p27Kip1 is one of the limiting factors that determine the sensitivity to Rap in already cycling cells. These data suggest the presence of a putative threshold level of p27Kip1 at late G1 phase in already cycling cells. Rap may cause G1 arrest by upregulating the amount of p27Kip1 beyond the threshold in some Rap-sensitive cells that are exponentially growing.
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PMID:The upregulation of p27Kip1 by rapamycin results in G1 arrest in exponentially growing T-cell lines. 942 10

Tyr-Phe and Met limitation in vitro inhibited cell proliferation and proliferating cell nuclear antigen (PCNA) expression to a greater extent than serum limitation. Tyr-Phe and serum limitation arrested cells in the G0/G1 phase; Met limitation blocked cells in the G0/G1 and S phases. Tyr-Phe limitation progressively decreased cyclin D1 expression to 30% of control within four days and did not affect expression of cyclin D3 or cyclin-dependent kinase (CDK2, CDK4, and CDK5) expression, Met limitation decreased cyclin D3 expression to 25% of control and CDK2 expression to 32% of control by Day 4 and did not affect expression of cyclin D1, CDK4, and CDK5. Serum limitation inhibited cyclin D1 and cyclin D3 expression to 24% of control after four days and did not effect CDK expression. Expression of two CDK inhibitors, p21WAF1/Cip1 and p27Kip1, was not changed by amino acid or serum limitation. Dietary restriction of Tyr-Phe in mice bearing subcutaneous B16BL6 melanoma tumors decreased tumor growth rate compared with mice fed a normal diet. Tumors from Tyr-Phe-restricted mice exhibited decreased PCNA expression, G0/G1 phase cell cycle arrest, and reduced cyclin D1 expression. These data indicate that decreased tumor growth in vivo associated with dietary restriction of Tyr and Phe is cell cycle specific.
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PMID:Tyrosine and phenylalanine restriction induces G0/G1 cell cycle arrest in murine melanoma in vitro and in vivo. 942 72

Progression through the G1/S transition of the cell cycle is regulated by cyclin E/cdk2 and cyclin A/cdk2 complexes. We demonstrate that there are two forms of murine cdk2 (cdk2 alpha and beta). Cdk2 alpha consist of 298 amino acids, while cdk2 beta contains a 48-amino-acid insert between Met (196) and Val (197) of cdk2 alpha. Cdk2 beta results from differential splicing of the primary RNA transcript of the cdk2 gene. Although human cdk2 genomic DNA contained the sequence of the insert for the beta form, cdk2 beta was not detected by either Western blot or RT-PCR in human T-cells or several other human cell lines. Cdk2 beta expression in murine cells was similar to that of the phosphorylated, catalytically active form of cdk2 alpha. Cdk2 alpha and cdk2 beta have very similar binding activity to cyclin E and to the cdk inhibitor p27Kip1. The alternatively spliced cdk2 beta possesses catalytic activity in vivo and in vitro. The differential catalytic activity of these two forms of cdk2 suggests that cdk2 alpha and cdk2 beta may perform different functions at or near the G1/S transition and early S phase.
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PMID:The differential catalytic activity of alternatively spliced cdk2 alpha and cdk2 beta in the G1/S transition and early S phase. 945 65

To understand the mechanism of interferon (IFN)-mediated suppression of cell cycle progression, we have earlier shown that IFN-alpha enhances the expression of underphosphorylated retinoblastoma protein by inhibiting the cyclin-dependent kinase-2 (CDK-2) activity (Kumar and Atlas, Proc. Natl. Acad. Sci. 89, 6599-6603, 1992; Zhang and Kumar, Biochem. Biophysi. Res. Comm., 200, 522-528, 1994). In the studies presented here, we investigated the mechanism of inhibition of CDKs in IFN-treated cells by delineating the potential role(s) of CDK-inhibitors (CKIs) and CDK-activating kinase (CAK). We report that IFN-alpha inhibits the H-1 kinase activity associated with CDK-4 or CDK-2 due to induction of expression of CDK-inhibitor p21WAF1 (but not p27Kip1) as its immunodepletion from IFN-treated extracts restored the CDK-associated H-1 kinase activity. In addition, we also show that IFN-gamma induces expression of CDK-inhibitors p21WAF1 and p27Kip1 and inhibited the H-1 kinase activity associated with CDK-2 or CDK-4. The observed IFN-gamma-mediated inhibition of CDK-2 and CDK-4 kinase activity was due to enhanced interactions with p21WAF1 and p27Kip1, respectively. We also demonstrated that IFN-induced CKIs prevent CAK from activating the CDK-2 as immunodepletion of induced CKIs from the inhibitory extracts resulted in the restoration of CAK-mediated activation of CDK-2.
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PMID:Interferon-induces expression of cyclin-dependent kinase-inhibitors p21WAF1 and p27Kip1 that prevent activation of cyclin-dependent kinase by CDK-activating kinase (CAK). 946 40


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