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 S/G2-specific transcription of the human cdc25C gene is due to the periodic occupation of a repressor element ('cell cycle-dependent element'; CDE) located in the region of the basal promoter. Protein binding to the major groove of the CDE in G0 and G1 results in a phase-specific repression of activated transcription. We now show that CDE-mediated repression is also the major principle underlying the periodic transcription of the human cyclin A and cdc2 genes. A single point mutation within the CDE results in a 10- to 20-fold deregulation in G0 and an almost complete loss of cell cycle regulation of all three genes. In addition, the cdc25C, cyclin A and cdc2 genes share an identical 5 bp region ('cell cycle genes homology region'; CHR) starting at an identical position, six nucleotides 3' to the CDE. Strikingly, mutation of the CHR region in each of the three promoters produces the same phenotype as the mutation of the CDE, i.e. a dramatic deregulation in G0. In agreement with these results, in vivo DMS footprinting showed the periodic occupation of the cyclin A CDE in the major groove, and of the CHR in the minor groove. Finally, all three genes bear conspicuous similarities in their upstream activating sequences (UAS). This applies in particular to the presence of NF-Y and Sp1 binding sites which, in the cdc25C gene, have been shown to be the targets of repression through the CDE.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression. 755 94

In quiescent cells, cdc2 mRNA is almost undetectable. Stimulation of cells to reenter the cell cycle results in induction of cdc2 expression, beginning at the G1-to-S transition and reaching maximum levels during late S and G2 phases. To investigate cdc2 transcriptional regulation throughout cell cycle progression, we monitored protein-DNA interactions by in vivo footprinting along 800 bp of the human cdc2 promoter in quiescent fibroblasts and at different time points following serum stimulation. We found 11 in vivo protein-binding sites, but no protein binding was observed at a high-affinity E2F site that had previously been implicated in cdc2 regulation. Nine of the identified in vivo binding sites (among them were two inverted CCAAT boxes, two Sp1 sites, and one ets-2 site) bind transcription factors constitutively throughout the cell cycle. However, at two elements located at positions -60 and -20 relative to the transcription start site, the binding pattern changes significantly as the cells are entering S phase. A G0- and G1-specific protein complex disappears at the -20 element at the beginning of S phase. This sequence deviates at one base position from known E2F consensus binding sites. We found that the major E2F activity in human fibroblasts contains E2F-4 and p130. The -20 element of the cdc2 gene specifically interacts with a subset of E2F-4-p130 complexes present in G0 cells but does not interact with S-phase-specific E2F complexes. Transient-transfection experiments with wild-type and mutant cdc2 promoter constructs indicate that the -20 element is involved in suppressing cdc2 activity in quiescent cells. We suggest that the presence of the p130-E2F-4 complex in G0/G1 blocks access of components of the basal transcription machinery or prevents transaction by the constitutively bound upstream activator proteins.
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PMID:In vivo structure of the human cdc2 promoter: release of a p130-E2F-4 complex from sequences immediately upstream of the transcription initiation site coincides with induction of cdc2 expression. 852 57

Cyclin-dependent protein kinases (Cdks) play a key role in the cell division cycle of eukaryotic cells. Cdc2, the first mammalian Cdk that was discovered, is expressed in S phase and functions in the G2 to M phase transition. By transfecting segments of the human cdc2 promoter linked to a reporter gene into monkey kidney (CV-1) cells, we identified the region containing the Sp1, E2F, and two CCAAT box binding sites as essential and sufficient for basal transcription. SV40 large T antigen (SV40-LT) is a viral oncoprotein that transactivates viral and cellular promoters and induces DNA synthesis in quiescent cells. SV40-LT transactivated wild-type cdc2 promoter/reporter constructs in a dose-dependent manner, coinciding with an increase in endogenous cdc2 mRNA. A mutant promoter from which the two CCAAT box motifs were deleted was 8-fold less sensitive to SV40-LT. Activation by SV40-LT did not require its ability to bind the retinoblastoma or p53 tumor suppressor proteins. SV40-LT induced a specific CCAAT box-binding factor (CBF) in CV-1 and COS-7 cells, as judged by gel shift and Southwestern analyses. Similar results were obtained in human fibroblasts expressing a conditional SV40-LT. The SV40-LT-inducible CBF appears to be novel and differs from the CBF that activates heat shock protein 70 gene expression.
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PMID:SV40 large T antigen transactivates the human cdc2 promoter by inducing a CCAAT box binding factor. 866 14

Cyclin D1 is a critical oncogene involved in the regulation of progression through the G1 phase of the cell cycle, thereby contributing to cell proliferation. This is mediated through interaction of cyclin D1 with its catalytic partners, the cyclin-dependent kinases, and the subsequent phosphorylation of the retinoblastoma protein. Cyclin D1, in turn, is regulated by mitogenic stimuli. We demonstrate that transforming growth factor-alpha (TGFalpha) induces cyclin D1 mRNA in esophageal squamous epithelial cells, and this appears to correlate with increased cyclin D1 protein expression and cyclin-dependent kinase 6 activity. The induction of cyclin D1 transcription by TGFalpha is mediated in part through the induction of the early growth response protein (Egr-1) and its subsequent binding of Egr-1 to a cis-regulatory region spanning nucleotides -144 to -104 of the cyclin D1 promoter. The Egr-1 binding activity to the cyclin D1 promoter appears to require de novo protein synthesis and is not influenced by Sp1 binding to overlapping Sp1 motifs. Taken together, these data provide evidence that TGFalpha enhances cyclin D1 transcription through the induction of Egr-1 binding to a cis-regulatory region in the cyclin D1 promoter. This has important mechanistic implications into the transcriptional regulation of cyclin D1 by an essential proproliferative growth factor and cell cycle progression.
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PMID:Transforming growth factor-alpha enhances cyclin D1 transcription through the binding of early growth response protein to a cis-regulatory element in the cyclin D1 promoter. 940 6

E2F transcription factors regulate the expression of a number of genes important in cell proliferation, particularly those involved in progression through G1 and into the S-phase of the cell cycle. The activity of E2F factors is regulated through association with the retinoblastoma tumor suppressor protein (Rb) and the other pocket proteins, p107 and p130. Binding of Rb, p107 or p130 converts E2F factors from transcriptional activators to transcriptional repressors. The interplay among G1 cyclins (D-type cyclins and cyclin E), cyclin-dependent kinases (cdk4, 6, and 2), cdk inhibitors, and protein phosphatases determines the phosphorylation state of the pocket proteins which in turn regulates the ability of the pocket proteins to complex with E2F. E2F activity is further regulated through direct interactions with other factors, such cyclin A, Sp1, p53 and the ubiquitin-proteasome pathway. Deregulated expression of E2F family member genes has been shown to induce both inappropriate S phase entry and apoptosis. An important role for E2F in the development of cancer is suggested by the finding that in most human neoplasias, genetic or epigenetic alterations occur that ultimately result in the deregulation of E2F-dependent transcription. This review will highlight recent findings on the specific roles of the individual E2F species in regulating transcription, proliferation and apoptosis, and discuss the growing link between E2F and cancer.
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PMID:Role of E2F in cell cycle control and cancer. 955 98

Differentiation of mammalian cells implies cessation of DNA replication and cell proliferation; the potential controls of this coupling are examined here. It is clear that the known or proposed mechanisms of down-regulation of replicative cellular activities vary in different lineages of cell differentiation, and occur in all phases of the cell cycle. In G1 these regulators include p21/Cip1 or p27/Kip1, pRb, and p53; the novel, recently reported mechanisms of their action are summarized. In S phase the availability of nucleotide precursors, the origin recognition complex (ORC), and other replication proteins may be important in differentiation, and in G2 phase the cdc2/cyclin B complex and replication licensing factors determine normal G2 traverse versus an arrest or polyploidisation. Other replication-related mechanisms include transcription factors, e.g., Sp1, telomerase, and nuclear matrix changes. Thus, differentiation alters the activity not only of the various checkpoint proteins, but also of the components of the replicative machinery itself.
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PMID:Differentiation-related mechanisms which suppress DNA replication. 1009 13

Fumonisin B1 (FB1) is a food-borne mycotoxin produced by Fusarium moniliforme. Structurally FB1 resembles sphingoid bases, and ingestion of FB1 causes several animal diseases. FB1 will cause hepatic carcinoma in rats and is implicated as a cofactor in esophageal or hepatic carcinoma. Previous studies concluded that FB1 repressed cyclin-dependent kinase 2 (CDK2) activity but induced CDK inhibitors p21(Waf1/Cip1), p27(Kip1), and p57(Kip2) in monkey kidney cells (CV-1). In contrast, CV-1 cells transformed by simian virus 40 are resistant to the antiproliferative or apoptotic effects of FB1. Consequently, FB1 treatment of CV-1 cells leads to cell cycle arrest and apoptosis. In this study, we demonstrate that FB1 transcriptionally activates the p21 promoter. Functional analysis of the p21 promoter by reporter gene assays mapped the FB1-responsive region to -124 to -47. DNase I footprinting analysis revealed two protected motifs that span the FB1-responsive region, -124 to -101 (footprint II) and -89 to -67 (footprint III). Further studies demonstrated that DNA sequences from -124 to -101 were sufficient for FB1 stimulation. DNA sequences from -124 to -101 contain two Sp1 binding sites, and gel shift assays provided evidence that nuclear factors specifically bind to this region. Disruption of the two Sp1 binding sites abrogated the binding of nuclear proteins and prevented activation by FB1. Taken together, these results suggest that Sp1 or Sp1-related proteins mediate FB1-induced activation of the p21 promoter.
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PMID:The mycotoxin fumonisin B1 transcriptionally activates the p21 promoter through a cis-acting element containing two Sp1 binding sites. 1021 8

Addition of nerve growth factor (NGF) to PC12 cells promotes neuronal differentiation while inhibiting cell proliferation. In order to understand how NGF exerts its antimitogenic effect during differentiation, we have studied the mechanism by which this factor activates the promoter of the CDK inhibitor p21W4F1/CIP1. The minimal region of the p21 promoter required for the NGF-induction was mapped to a contiguous stretch of 10 bp located 83 bases upstream of the transcription initiation site. This GC-rich region was shown to interact specifically with the transcription factor Sp1 and the related protein Sp3, in either exponentially-growing or NGF-treated PC12 cells. The addition of NGF resulted in an accumulation of the transcriptional co-activator p300 in complexes associated with the NGF-responsive region. Transcriptional activity of Sp1, Sp3 and p300 was specifically induced by NGF in a Gal4-fusion assay, indicating that induction of p21 during neuronal differentiation may involve regulation of the activity of these factors by NGF. Furthermore, p300 was able to act as a co-activator for Sp1-mediated transcriptional activation in PC12 cells, suggesting that p300 and Sp1 may cooperate in activating p21 transcription during the withdrawal of neuronal precursors from the cell cycle. This hypothesis is supported by experiments showing that p300 and Sp1 form complexes in PC12 cells.
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PMID:Cooperation of Sp1 and p300 in the induction of the CDK inhibitor p21WAF1/CIP1 during NGF-mediated neuronal differentiation. 1036 58

This review is focused on recent investigations demonstrating a pharmacological and pathophysiologic role in gastroduodenal ulceration for growth factors such as basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), as well as for transcription factors. Our experiments revealed accelerated healing, without decreased gastric acid secretion, of chronic cysteamine-induced duodenal ulcers in rats treated daily for 3 weeks with intragastric administration of bFGF, PDGF or VEGF. Our recent studies also indicate a pathophysiological role of endogenous growth factors in the natural history of experimental duodenal ulcer development and healing. More recently, we investigated the genetic regulation of these growth factors in experimental duodenal ulceration. Since gene expression is most effectively controlled by transcription factors, proteins that bind to cis-acting elements of DNA and guide the binding of polymerase II to start the transcription of specific mRNA, we tested the hypothesis that the expression of IEGs and their transcription factor products, such as Egr-1 and Sp1, might precede the increased synthesis of bFGF, PDGF and VEGF in duodenal ulcer healing. Indeed, the duodenal ulcerogen cysteamine, but not its nonulcerogen and toxic analogue ethanolamine, rapidly increased duodenal (but not gastric) mucosal levels of ET-1, which was followed by enhanced expression of Egr-1 and a decrease in Sp1 in the preulcerogenic stage of duodenal ulceration. These changes in levels of ET-1 and expression of transcription factors were also accompanied by increased expression of the CDK inhibitor p21. Thus, not only growth factors such as bFGF, PDGF and VEGF, but also transcription factors such as Egr-1 and Sp1 and the cell cycle regulator p21, may play a role in the natural history of experimental duodenal ulceration.
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PMID:Review article: transcription factors and growth factors in ulcer healing. 1080 1

Schwann cell proliferation is regulated by multiple growth factors and axonal signals. However, the molecules that control growth arrest of Schwann cells are not well defined. Here we describe regulation of the cyclin-dependent kinase-2 (CDK2) protein, an enzyme that is necessary for the transition from G1 to S phase. Levels of CDK2 protein were elevated in proliferating Schwann cells cultured in serum and forskolin. However, when cells were grown with either serum-free media or at high densities, CDK2 levels declined to low levels. The decrease in CDK2 levels was associated with growth arrest of Schwann cells. The modulation of CDK2 appears to be regulated at the transcriptional level, because CDK2 mRNA levels and its promoter activity both decline during cell cycle arrest. Furthermore, analysis of the CDK2 promoter suggests that Sp1 DNA binding sites are essential for maximal activation in Schwann cells. Together, these data suggest that CDK2 may represent a significant target of developmental signals that regulate Schwann cell proliferation and that this regulation is mediated, in part, through regulation of Sp1 transcriptional activity.
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PMID:Cell cycle control of Schwann cell proliferation: role of cyclin-dependent kinase-2. 1084 32


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