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 mammalian transcription factor E2F plays a critical role in the expression of genes required for cellular proliferation. To understand how E2F is regulated, we have developed a reconstituted in vitro transcription assay. Using this E2F-responsive assay, we can demonstrate that E2F-mediated transcription can be directly repressed by the tumor suppressor protein pRB. This inhibition is abolished by phosphorylation of pRB with either cyclin A/cdk2 or cyclin E/cdk2. However, these cyclin/kinase complexes exhibit differences in the ability to phosphorylate E2F. Only cyclin A/cdk2 can phosphorylate E2F effectively, and this phosphorylation abolishes its ability to bind DNA and mediate trans-activation. Thus, this in vitro transcriptional assay allows activation and inactivation of E2F transcription, and our findings demonstrate how transcriptional regulation of E2F can be linked to cell cycle-dependent activation of kinases.
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PMID:Differential regulation of E2F transactivation by cyclin/cdk2 complexes. 795 56

We have analysed the expression of 7 cyclin and cyclin-associated kinase (cdk) genes in the human myeloid cell line HL-60 at different stages of the cell cycle in non-synchronised cells and during terminal differentiation. A clear cell cycle-dependent expression was found with cyclins A (S+G2), B (G2) and E (late G1 and S), while other cell cycle genes showed only very weak (cdk2) or no periodic expression (cyclin D1, cyclin D2 and cdk4). Induction of macrophage-like differentiation by TPA or granulocytic differentiation by retinoic acid or DMSO was accompanied by a block in G1 and resulted in distinct patterns of gene expression that were lineage- and inducer-specific. These included: (i) a dramatic decrease in the expression of cyclin A, cyclin B and cdk2, and surprisingly an up-regulation of cyclin D1 in TPA-induced macrophage-like cells; (ii) a down-regulation of cyclin E in retinoic acid-induced granulocytic cells; and (iii) a decreased abundance of cyclin D1 and D2, but high levels of cyclin A, B and E RNA in DMSO-induced granulocytic cells. These observations suggest that the mechanisms leading to a differentiation-associated cell cycle arrest are lineage-specific, and that the sustained expression of cyclin and cdk genes does not interfere with the induction of terminal differentiation.
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PMID:Lineage-specific regulation of cell cycle gene expression in differentiating myeloid cells. 798 66

The cyclin-dependent kinase (Cdk) enzymes, when associated with the G1 cyclins D and E, are rate-limiting for entry into the S phase of the cell cycle. During T-cell mitogenesis, antigen-receptor signalling promotes synthesis of cyclin E and its catalytic partner, Cdk2, and interleukin-2 (IL-2) signalling activates cyclin E/Cdk2 complexes. Rapamycin is a potent immunosuppressant which specifically inhibits G1-to-S-phase progression, leading to cell-cycle arrest in yeast and mammals. Here we report that IL-2 allows Cdk activation by causing the elimination of the Cdk inhibitor protein p27Kip1, and that this is prevented by rapamycin. By contrast, the Cdk inhibitor p21 is induced by IL-2 and this induction is blocked by rapamycin. Our results show that p27Kip1 governs Cdk activity during the transition from quiescence to S phase in T lymphocytes and that p21 function may be restricted to cycling cells.
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PMID:Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. 799 Sep 32

Fumagillin analogue AGM-1470 potently inhibits angiogenesis with a minimal toxicity in vivo and is expected to be of therapeutic use as a powerful antitumor agent (Ingber et al., Nature, 348:555-557, 1990). In the present study, we have investigated the effects and the mechanism of action of AGM-1470 on cultured human umbilical vein endothelial cells. AGM-1470 acts directly on endothelial cells to inhibit growth factor-induced DNA synthesis, with half maximal and maximal effects obtained at approximately 2 x 10(-10) and 5 x 10(-9) M, respectively. AGM-1470 does not inhibit early G1 mitogenic events, such as cellular protein tyrosyl phosphorylation or the expression of immediate early genes c-fos and c-myc, but potently inhibits phosphorylation of RB protein, a tumor suppressor retinoblastoma gene product. The later addition of AGM-1470 up to 3 h after the growth factor stimulation still exerts full inhibitory effects on both DNA synthesis and RB phosphorylation, suggesting that the major site of action of AGM-1470 is located relatively late in the G1 phase. AGM-1470 inhibits growth factor-induced activation of candidate RB kinases cdc2 and cdk2 but fails to inhibit them directly in vitro. AGM-1470 completely abolishes the growth factor-induced mRNA expression of cdc2 and cyclin A and partially inhibits that of cyclin E but has little effect on the mRNA level of cdk2, cdk4, or cyclin D1. These results indicate that angioinhibitory action of AGM-1470 involves suppression of mRNA expression of specific members of cdks and cyclins and of activation of both cdc2 and cdk2 kinases in endothelial cells.
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PMID:A fumagillin derivative angiogenesis inhibitor, AGM-1470, inhibits activation of cyclin-dependent kinases and phosphorylation of retinoblastoma gene product but not protein tyrosyl phosphorylation or protooncogene expression in vascular endothelial cells. 801 59

We cloned p27Kip1, a cyclin-dependent kinase inhibitor implicated in G1 phase arrest by TGF beta and cell-cell contact. p27Kip1 associates with cyclin E-Cdk2 complexes in vivo and in vitro, prevents their activation, and inhibits previously activated complexes, and p27Kip1 overexpression obstructs cell entry into S phase. p27Kip1 potently inhibits Rb phosphorylation by cyclin E-Cdk2, cyclin A-Cdk2, and cyclin D2-Cdk4. p27Kip1 is highly conserved and broadly expressed in human tissues, and its mRNA levels are similar in proliferating and quiescent cells. p27Kip1 has a region of sequence similarity to p21Cip1/WAF1, the Cdk inhibitor whose transcription is stimulated by p53. A p27Kip1 peptide corresponding to this region retains Cdk inhibitory activity. We suggest that cell contact, TGF beta, and p53 all restrain cell proliferation through related Cdk inhibitors.
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PMID:Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. 803 12

Using a yeast interaction screen to search for proteins that interact with cyclin D1-Cdk4, we identified a 27 kDa mouse protein related to the p21 cyclin-Cdk inhibitor. p27 interacts strongly with D-type cyclins and Cdk4 in vitro and more weakly with cyclin E and Cdk2. In mouse fibroblasts, p27 is associated predominantly with cyclin D1-Cdk4. Recombinant p27 is a potent inhibitor of cyclin D1-Cdk4 and cyclin A-Cdk2 protein kinase activity and a weaker inhibitor of cyclin B1-Cdc2. Overexpression of p27 in Saos-2 cells causes G1 arrest. p27 protein levels do not change as serum-stimulated quiescent mouse fibroblasts progress through the cell cycle. p27 is identical to p27Kip1, a cyclin-Cdk inhibitor present in TGF beta-treated cells. p27 has the hallmarks of a negative regulator of G1 progression and may mediate TGF beta-induced G1 arrest.
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PMID:p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. 803 13

In this study we have surveyed by immunoblotting the protein levels of Cyclin D1, D2, D3 and their catalytic partners, Cdk4 and Cdk6 in normal and transformed human cells. We found that all these proteins were differentially expressed in diploid cells derived from different tissues, in contrast to Cyclin E, Cyclin A and Cdk2 which are ubiquitously expressed. D-type Cyclins were never dramatically overexpressed and often very poorly expressed in tumor cell lines when compared to the levels in their normal counterparts. In contrast, Cdk4 was expressed at high levels in several tumor cell lines and Cdk6 was ectopically expressed in two sarcoma lines, suggesting a possible involvement of these two Cdks in oncogenesis. Interestingly, low levels of Cyclin D1 and D3 proteins always correlated with functional inactivation of the retinoblastoma gene product (pRb). In cells displaying active pRb, Cyclin D1 was found associated with Cdk4 regardless of whether the p53 gene was wild-type or mutant. Microinjection during G1 of Cyclin D1 anti-sense cDNA or anti-Cyclin D1 antibody in these cells arrested the cell cycle in G1. In cells lacking pRb function, Cyclin D1 was dissociated from Cdk4. Microinjection during G1 of Cyclin D1 antisense cDNA or anti-Cyclin D1 antibody in these cells did not affect G1 progression. These results show that (i) in the absence of pRb, Cyclin D1 is expressed at low levels, is dissociated from Cdk4 and becomes dispensable in G1; (ii) Cyclin D1 needs to be associated with its catalytic subunit, Cdk4, to function as a positive regulator of G1 progression.
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PMID:Differential expression and regulation of Cyclin D1 protein in normal and tumor human cells: association with Cdk4 is required for Cyclin D1 function in G1 progression. 805 30

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

Differentiation induction by 12-o-tetradecanoyl 13-acetate (TPA) results in the growth arrest of HL60 cells in the G1 phase. However, little is known about the changes of cell cycle-regulating genes during this differentiation process. We investigated the changes of mRNA for various cyclins (A, C, D1, D2, D3 and E) and cdk2. Synchronized HL60 cells began to proliferate immediately after release from cell cycle block and cell cycle synchrony was obvious until the second S phase. TPA-treated cells accumulated in G1 phase within 24 h and most of the cells were arrested in this phase at 36 h. The expression of cyclins and cdk2 was studied by Northern blot hybridization of the reverse-transcription polymerase chain reaction (RT-PCR). TPA treatment altered the expression of all genes studied. The expression of cdk2 and cyclin A mRNA was markedly down-regulated. Cyclin E mRNA expression was also prominently down-regulated from 12 h to 36 h, at which time a second increase of its expression was observed in control cells. In contrast, the expression of cyclin D1 mRNA was induced by TPA, while its expression in control cells was undetectable by Northern blot hybridization throughout the cell cycle. Cyclin C expression was faint and fluctuated irrelevant of cell cycle, but its expression in both control and TPA-treated cells was higher than at baseline. Cyclin D2 expression remained stable in control cells and TPA treatment resulted in slight down-regulation at 12 h, but no difference was observed after 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes of G1 cyclins, cdk2, and cyclin A during the differentiation of HL60 cells induced by TPA. 807 6

Cyclin E is a cell cycle-regulated protein that activates the cdc2-related protein kinases cdk2 shortly before S-phase entry. In order to analyse the biological role of cyclin E, we have generated HeLa cells that allow the conditional expression of ectopic human cyclin E. In these cells, a cyclin E cDNA is under the control of a bacterial tetracycline repressor-VP16 activator hybrid protein. In the absence of tetracycline, the endogenous gene becomes activated and leads to the synthesis of elevated levels of cyclin E. Concomitant with this increase in cyclin E expression we show by a combined time-lapse video recording/5-bromo-deoxyuridine labelling procedure a significant acceleration of G1 transition by approximately 1.5 hours. This observation is consistent with the idea that cyclin E is a rate-limiting factor with respect to the control of G1-->S transition. The experimental system described here should also prove useful to address the function of cyclin E in further detail.
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PMID:Inducible acceleration of G1 progression through tetracycline-regulated expression of human cyclin E. 810 47


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