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)

Alpha interferon is a potent growth inhibitor of Daudi Burkitt's lymphoma cells. We show here that alpha-interferon signaling interacted simultaneously with several components of the basic cell cycle machinery, causing cells to enter into a state that had many features characteristic of the G0 state. Within a few hours after alpha-interferon treatment, cyclin D3 mRNA and protein levels dropped to undetectable levels and, in parallel, the activities of cyclin A- and cyclin E-associated kinases were significantly reduced. The latter resulted from the rapid alpha-interferon-mediated elimination of cdc25A, a phosphatase that is required for antagonism of negative tyrosine phosphorylation of cdk2 in cyclin-cdk complexes. This regulation represents a novel mechanism through which an external inhibitory cytokine interacts with the cell cycle machinery. At later time points after alpha-interferon treatment, the levels of the 55-kDa slowly migrating hyperphosphorylated form of cyclin E and of cyclin A were also reduced. The antiproliferative effects were reversible, and cultures from which alpha interferon was removed reentered S phase after a lag that typically corresponded to approximately two doubling times. During this lag period, the expression of cyclin D3 and cyclin A, as well as of the cdc25A phosphatase, continued to be switched off, in spite of the removal of alpha interferon from the cell surface. In contrast, c-myc, which represents another downstream target gene that is subjected to negative regulation by alpha interferon, was relieved from suppression much earlier, concomitant with the decay in early signaling of the cytokine. The delayed pattern of cyclin reexpression provides evidence that alpha-interferon signaling imposes a G0-like state on this system.
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PMID:Alpha interferon suppresses the cyclin D3 and cdc25A genes, leading to a reversible G0-like arrest. 866 11

We have investigated the regulation of p27kip1, a cyclin-dependent kinase inhibitor, in BALB/c 3T3 cells during growth factor-stimulated transition from quiescence (G0) to a proliferative (G1) state. The level of p27kip1 protein falls dramatically after mitogenic stimulation and is accompanied by a decrease in cyclin E associated p27kip1, as well as a transient increase in cyclin D1-associated p27kip1 that later declines concomitantly with the loss of total p27kip1. Analysis of metabolically labelled cells revealed that cyclin D2, cyclin D3, and cdk4 were also partnered with p27kip1 in quiescent BALB/c 3T3 cells and that this association decreased after platelet-derived growth factor (PDGF) treatment. Furthermore, the decline in p27kip1 and reduced association with cyclin D3, initiated by the addition of PDGF but not plasma-derived factors, suggested that these changes are involved in competence, the first step in the exit from G0. Synthesis of p27kip1 as determined by incorporation of [35S]methionine was repressed upon mitogenic stimulation, and PDGF was sufficient to elicit this repression within 2 to 3 h. Pulse-chase experiments demonstrated the reduced rate of synthesis was not the result of an increased rate of degradation. Full repression of p27kip1 synthesis required the continued presence of PDGF and failed to occur in the presence of the RNA polymerase inhibitor 5,6-dichlorobenzimidazole riboside. These characteristics demonstrate that repression was a late effect of PDGF and was consistent with our finding that conditional expression of activated H-ras did not affect synthesis of p27kip1. Northern (RNA) analysis of p27kip1 mRNA revealed that the repression was not accompanied by a corresponding decrease in p27kip1 mRNA, suggesting that the PDGF-regulated decrease in p27kip1 expression occurred through a translational mechanism.
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PMID:Repression of p27kip1 synthesis by platelet-derived growth factor in BALB/c 3T3 cells. 875 33

The activity of the E2 F-family of transcription factors is tightly linked to control of the cell cycle. p107 and p130, two closely related members of the retinoblastoma protein-family of negative cell cycle regulators, modulate the activity of the E2f-family proteins by direct interaction with these factors. To understand the role of p107 and p130 in progression through or exit from the cell cycle, we have characterized the expression, phosphorylation state, cyclin-binding, and E2f-binding activity of p107 and p130 during terminal differentiation of rat myoblast cells into immature skeletal muscle (myotubes). In exponentially growing L6 myoblasts, p107 is phosphorylated in a cell cycle-dependent manner, and E2f-site binding complexes containing p107 is phosphorylated in a cell cycle-dependent manner, and E2f-site binding complexes containing p107 can be observed throughout the cell cycle. During differentiation of L6 cells, p107 levels are reduced, while p130 protein levels are increased 8-fold. Despite both p107 and p130 becoming hypophosphorylated during myogenesis, the E2F-site DNA-binding complexes containing p107 observed in exponentially growing myoblasts are quantitatively replaced in myotubes with complexes containing only p130. In myotubes, p107 is not associated with E2f-family proteins that are capable of binding DNA. The failure to observe p107-containing complexes in myotubes appears to be due to the differentiation-specific induction of both p130 and cyclin D3, p107 is found in complexes with cyclin D3 in myotubes, and the addition of exogenous cyclin D3 or p130 to lysates from undifferentiated L6 cells was able to disrupt p107-containing E2F-site binding complexes. In myotubes, p130 also forms complexes with cyclin D3 as well as cyclin E, cdk2, and cdk4. We are able to copurify cyclin D3 with cyclin E from myotubes, indicating the presence of a macromolecular complex containing both cyclin E and cyclin D3 simultaneously bound to p130. Thus, in myoblasts, p107 is normally involved in regulation of E2f-family proteins during cell cycle progression, while p130 is a differentiation-specific regulator of E2f activity. Our results also provide evidence that the apparent positive regulator of cell cycle progression, cyclin D3, has a function in terminally differentiated muscle cells.
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PMID:Expression and activity of the retinoblastoma protein (pRB)-family proteins, p107 and p130, during L6 myoblast differentiation. 884 6

Cell-cycle progression in somatic cells is regulated by a family of cyclins and cyclindependent kinases (cdks) that form specific complexes as a function of cell-cycle progression. However, the transcript abundance of G1-S cyclins and cdks during the meiotic and mitotic cell cycles of mammalian embryos has not been previously reported. Using a reverse transcription-polymerase chain reaction (PCR) assay that detects changes in either mRNA abundance or polyadenylation state, we examined the relative levels of gene expression for the G1-S cyclins and cdks, as well as for p21, p27, and the retinoblastoma (Rb) gene in mouse oocytes, metaphase II-arrested eggs, and 1-2-cell embryos. The PCR products for cyclins D1, D3, and A, as well as cdk4, p21, and Rb, displayed similar levels in meiotically incompetent and competent oocytes, as well as in metaphase II-arrested eggs. The levels of PCR products for cyclin D2, p27, and two forms of cdk2 were similar in meiotically incompetent and competent oocytes but decreased during oocyte maturation. Finally, the level of PCR products for cyclin E and cdk2 gradually decreased during the progression from meiotically incompetent oocytes to metaphase II-arrested eggs. When the levels of PCR products for the G1-S regulatory genes were evaluated during the first and second mitotic cell cycles, four main patterns were found: 1) steady levels for cyclin A; 2) steady levels followed by a 2-3-fold increase during the G2 phase of the second mitotic cell cycle for cyclins D1, E, cdk2, and p21; 3) a transient increase during the S and/or G2 phases of the first mitotic cell cycle for p27, cyclin D3, and the two forms of cdk2; and 4) higher levels during the first cell cycle and then a decrease with lower levels during the second mitotic cell cycle for cyclin D2 and Rb. cdk4 expression displayed a combination of patterns 2 and 3. The increase in the amount of PCR product for the cdk4 gene during the first mitotic cell cycle was due to polyadenylation, whereas the increase in the amount of PCR product for cdk4, cdk2, and cyclins D1 and E in the second mitotic cell cycle was a product of activation of the embryonic genome.
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PMID:Temporal patterns of gene expression of G1-S cyclins and cdks during the first and second mitotic cell cycles in mouse embryos. 891 36

The retinoblastoma protein (Rb) is essential for the maintenance of the postmitotic state in terminally differentiated myocytes. Upon C2C12 myogenesis, the level of the cyclin-dependent kinase 4 (CDK4) protein does not change, but its Rb kinase activity is down-regulated markedly. Here, we show that the reduction in CDK4 activity results from (a) the irreversible induction and association of the p21 CDK inhibitor with the CDK4 complex and (b) a decline in overall D-type cyclin expression. Immunoprecipitation-coupled immunoblot analyses demonstrated that myocyte differentiation produces alterations in the subunit interactions within the CDK4 complex, including a diminished interaction with cyclin D1 and enhanced interactions with cyclin D3 and p21. The significance of the p21 interaction with CDK4 was indicated by the ability of anti-p21 antibodies to specifically immunodeplete a Rb kinase inhibitory activity that was bound to the CDK4 complex in myotubes. Furthermore, the restimulation of myotubes with serum did not lead to the re-activation of CDK4 or disrupt the CDK4-p21 interaction. Despite the increase in cyclin D3 expression during myogenesis, quantitative immunoblot analyses revealed that the combined levels of cyclin D1 and D3 decline during this process and that CDK4 is expressed at much higher levels than either of these cyclin subunits in postmitotic myotubes. These results suggest that the myogenesis-induced up-regulation of p21 and down-regulation of the total D-type cyclin expression contribute to the inhibition of the CDK4 Rb kinase activity, leading to conditions that favor the accumulation of the hypophosphorylated Rb and growth arrest upon terminal differentiation.
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PMID:Inhibition of retinoblastoma protein phosphorylation by myogenesis-induced changes in the subunit composition of the cyclin-dependent kinase 4 complex. 893 Mar 96

In order to better understand the molecular background of differences between the clinical picture of T- and B-lineage ALLs, we studied the expression of several proteins involved in the regulation of cell proliferation in bone marrow blast cells from 30 cases of previously untreated acute lymphoblastic leukaemia (ALL); 14 cases were T- and 16 B-cell lineage ALLs. We studied several cyclin-dependent kinases (cdk1, cdk2, cdk4, cdk6) and cyclins (cyclin A, cyclin B1, cyclin D3 and cyclin E). We also studied proliferating cell nuclear antigen (PCNA) and Bcl-2 expression, the latter protein known to be involved in the prolonged survival of B-lineage ALL blasts. Proteins obtained from cell lysates were resolved on polyacrylamide gel followed by immunodetection and densitometry of specific bands. Expression of cdk1 and PCNA, markers of proliferative activity, was significantly higher in T- than in B-lineage ALL. Cdk6, which was highly correlated to PCNA, was also higher in T-cell ALL. In contrast, B-lineage ALL displayed a higher expression of anti-apoptotic protein Bcl-2. We hypothesize that those particularities may reflect differential roles of cell multiplication and apoptosis in the neoplastic proliferation of B- and T-lineage ALL.
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PMID:Differential expression of cell proliferation regulatory proteins in B- and T-lineage acute lymphoblastic leukaemias. 894 94

Cellular proliferation is an essential aspect of chemical carcinogenesis. At the core of cell cycle regulation is a family of serine/threonine protein kinases termed cyclin-dependent kinases (cdk). Cdk activity, which directs progression through the cell cycle, is dependent upon cdk binding to the appropriate, phase-specific cyclin proteins. Alterations in hepatic cdk1, cdk2, cdk4, cdk5, and cyclin protein expression were determined in response to acute dosing of the prototypic peroxisome proliferator and hepatocarcinogen [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (WY14,643). Intraperitoneal dosing of 45 mg WY14,643/kg daily for 4 days to young, male rats produced dramatic increases in hepatic protein expression of all cdk analyzed as well as cyclins B, D2, D3, and proliferating cell nuclear antigen (PCNA). The largest relative increases, 6.1-, 2.8-, 11-, 83-, and 7.9-fold, were seen with cdk1, cdk4, cyclin B, cyclin D3, and PCNA, respectively. Increases of only 1.8-, 2-, 1.6-, and 1.4-fold were noted, respectively, for cdk2, cdk5, cyclin D2, and cyclin E. Analysis of gel filtration fractions indicated that PCNA co-eluted with cdk1 from the WY14,643-treated rats as a 70-80 kDa molecular complex. In contrast, cdk4, cdk5 and D cyclins migrated as much larger complexes with an estimated MW of approximately 180-190 kDa.
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PMID:Discordant expression of the cyclin-dependent kinases and cyclins in rat liver following acute administration of the hepatocarcinogen [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (WY14,643). 898 38

We previously showed that C2 myoblasts transformed by simian virus 40 large T antigen (SVLT) stop the myogenic process after the induction of myogenin and of high Rb levels; the induced Rb, however, becomes notably phosphorylated. We have analyzed the protein levels and activities of cyclin-dependent kinases (cdks) in untransformed C2 cells and in transformants of either SVLT or the cytoplasmic mutant NKT1 (which permits differentiation) upon a shift from growth medium (GM) to mitogen-poor differentiation medium (DM). After the shift, cdk4 levels remained constant and cdk6 levels decreased in all cell types; cdk2 minimally increased only in SVLT cells. Cyclin D1 was downregulated in DM in all cell types, and cyclin D3 was upregulated (albeit less strongly in SVLT cells than in the others). In contrast, a dramatic difference between SVLT cells and the other cells was observed for cyclins E and A, which essentially disappeared (as protein and RNA) in normal C2 and NKT1 cells upon the shift from GM to DM, whereas they increased in SVLT cells. Concurrently, cdk2 activity ceased in C2 and NKT1 cells in DM, whereas it persisted at 20% of the GM level in SVLT cells. cdk4 activity was detectable in all cells only in GM. Cyclin E and A induction thus appeared to sustain enough Rb phosphorylation to interfere with tissue-specific expression, with cdk activity not high enough to activate cyclin self-regulation. In DM, cdk2 complexed to D3 was underphosphorylated in all cells, and SVLT allowed strong inductions of p21 and p27 without affecting their complexes with cdks.
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PMID:Induction of cyclins E and A in response to mitogen removal: a basic alteration associated with the arrest of differentiation of C2 myoblasts transformed by simian virus 40 large T antigen. 903 56

The family of cyclins and cyclin-dependent kinases (CDKs) are important participants in the regulation of eukaryotic cell cycle. Our purpose was to examine temporal expressions of cyclins and CDKs during renal development and compensatory growth. During embryonic development the mRNA levels of all cyclins were high, and after birth their levels decreased at different rates. G2 and M phase cyclins, cyclin A and B, decreased immediately after birth. G1 and S phase cyclins, cyclins D1, D2, D3, and E, were observed during all stages of development and maintained almost constant levels until seven days after birth. They decreased thereafter and expressed very low levels during the adult period. The protein levels of cdc2, CDK2, and proliferating cell nuclear antigen (PCNA) were high during embryonic renal development and slowly decreased after birth. Their levels were very low during the youth and adult periods. Levels of CDK4 protein were high and did not change during renal development. Compensatory hypertrophic renal growth (CHRG) induced by unilateral nephrectomy (Unx) did not increase any cyclins, CDKs or PCNA. Subtotal nephrectomy (Snx) did not increase any cyclins or CDKs in remaining viable renal tissue (RVRT). However, Snx increased PCNA in RVRT. An immunohistochemical study revealed that PCNA was induced in a limited area adjacent to ischemic areas. Interestingly, Western blot analysis of protein extracts from RVRT showed the induction of a new 40 kDa protein that cross-reacted with the cyclin D3 antibody. These findings suggest that the marked reductions in mitotic cyclins may be associated with the withdrawal of renal cell cycle after birth. In addition, expressions of cyclins and CDKs did not change in the adult kidney during active phase of compensatory hypertrophic growth.
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PMID:Temporal expressions of cyclins and cyclin dependent kinases during renal development and compensatory growth. 906 8

IL-4 activates resting B cells and, in conjunction with cosignals such as anti-IgM (anti-mu) Ab or CD40 ligand, modulates progression of B cells through the cell cycle, leading to proliferation. In this study, we show that the mitogenic combination of IL-4 and anti-mu Ab triggered induction of cyclin D3 and up-regulated cyclin-dependent kinase (cdk) 6 expression, whereas such regulation was not observed in B cells activated by IL-4 or anti-mu Ab alone. Furthermore, cyclin D3 immunoprecipitated fron as associated with cdk6, and the cyclin D3/cdk6 complex was able to phosphorylate recombinant retinoblastoma protein in vitro. In addition, B cells activated with either IL-4 or 1L-13 alone expressed a higher amount of p27kip1 (p27) cdk inhibitor than nonstimulated cells. In contrast, p27 expression was decreased when cells were activated with mitogenic combinations of IL-4 and anti-mu Ab or anti-CD40 mAb. We also observed that the IL-4-mediated inhibition of the proliferation of anti-mu/IL-2- or anti-mu/phorbol 12,13-dibutyrate-activated human leukemic B cells was associated with the maintenance of large amounts of p27 in these cells. These data suggest that IL-4 controls B cell proliferation by action during at least two steps of the regulation of the cell cycle, cyclin D3/cdk6 complex regulation and p27 inhibitor expression.
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PMID:Modulation of the p27kip1 cyclin-dependent kinase inhibitor expression during IL-4-mediated human B cell activation. 912 Feb 57


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