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 kinase activities of the cyclin/cdk complexes can be regulated in a number of ways. The most recently discovered mechanism of regulation is the association of cdk inhibitors (CKIs), such as p21, p27, and p57, with these complexes. In this report we demonstrate that the pRB-related protein p107, like the p21 family of cdk inhibitors, can inhibit the phosphorylation of target substrates by cyclin A/cdk2 and cyclin E/cdk2 complexes, and the associations of p107 and p21 with cyclin/cdk2 rely on a structurally and functionally related interaction domain. Furthermore, interactions between p107 or p21 with cyclin/cdk2 complexes are mutually exclusive. In cells treated with DNA-damaging agents elevated levels of p21 cause a dissociation of p107/cyclin/cdk2 complexes to yield p21/cyclin/cdk2 complexes. Finally, the consequences of cyclin/cdk2 interactions with p107 have been examined. The activation of the p107-bound cyclin/cdk kinases leads to dissociation of p107 from the transcription factor E2F. Together, these results suggest that cyclin/cdk complexes can be regulated by protein molecules from different families in a mutually exclusive manner in response to certain signals and that these inhibitory proteins may have a potential role in regulating macromolecular assembly.
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PMID:p107 uses a p21CIP1-related domain to bind cyclin/cdk2 and regulate interactions with E2F. 762 38

Progression through the cell cycle is catalyzed by cyclin-dependent kinases (CDKs) and is negatively controlled by CDK inhibitors (CDIs). We have isolated a new member of the p21CIP1/p27KIP1 CDI family and named it p57KIP2 to denote its apparent molecular mass and higher similarity to p27KIP1. Three distinct p57 cDNAs were cloned that differ at the start of their open reading frames and correspond to messages generated by the use of distinct splice acceptor sites. p57 is distinguished from p21 and p27 by its unique domain structure. Four distinct domains follow the heterogeneous amino-terminal region and include, in order, a p21/p27-related CDK inhibitory domain, a proline-rich (28% proline) domain, an acidic (36% glutamic or aspartic acid) domain, and a carboxy-terminal nuclear targeting domain that contains a putative CDK phosphorylation site and has sequence similarity to p27 but not to p21. Most of the acidic domain consists of a novel, tandemly repeated 4-amino acid motif. p57 is a potent inhibitor of G1- and S-phase CDKs (cyclin E-cdk2, cyclin D2-cdk4, and cyclin A-cdk2) and, to lesser extent, of the mitotic cyclin B-Cdc2. In mammalian cells, p57 localizes to the nucleus, associates with G1 CDK components, and its overexpression causes a complete cell cycle arrest in G1 phase. In contrast to the widespread expression of p21 and p27 in human tissues, p57 is expressed in a tissue-specific manner, as a 1.5-kb species in placenta and at lower levels in various other tissues and a 7-kb mRNA species observed in skeletal muscle and heart. The expression pattern and unique domain structure of p57 suggest that this CDI may play a specialized role in cell cycle control.
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PMID:Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. 772 83

We have isolated Xenopus p28Kix1, a member of the p21CIP1/p27KIP1/p57KIP2 family of cyclin-dependent kinase (Cdk) inhibitors. Members of this family negatively regulate cell cycle progression in mammalian cells by inhibiting the activities of Cdks. p28 shows significant sequence homology with p21, p27, and p57 in its N-terminal region, where the Cdk inhibition domain is known to reside. In contrast, the C-terminal domain of p28 is distinct from that of p21, p27, and p57. In co-immunoprecipitation experiments, p28 was found to be associated with Cdk2, cyclin E, and cyclin A, but not the Cdc2/cyclin B complex in Xenopus egg extracts. Xenopus p28 associates with the proliferating cell nuclear antigen, but with a substantially lower affinity than human p21. In kinase assays with recombinant Cdks, p28 inhibits pre-activated Cdk2/cyclin E and Cdk2/cyclin A, but not Cdc2/cyclin B. However, at high concentrations, p28 does prevent the activation of Cdc2/cyclin B by the Cdk-activating kinase. Consistent with the role of p28 as a Cdk inhibitor, recombinant p28 elicits an inhibition of both DNA replication and mitosis upon addition to egg extracts, indicating that it can regulate multiple cell cycle transitions. The level of p28 protein shows a dramatic developmental profile: it is low in Xenopus oocytes, eggs, and embryos up to stage 11, but increases approximately 100-fold between stages 12 and 13, and remains high thereafter. The induction of p28 expression temporally coincides with late gastrulation. Thus, although p28 may play only a limited role during the early embryonic cleavages, it may function later in development to establish a somatic type of cell cycle. Taken together, our results indicate that Xenopus p28 is a new member of the p21/p27/p57 class of Cdk inhibitors, and that it may play a role in developmental processes.
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PMID:Cell cycle control by Xenopus p28Kix1, a developmentally regulated inhibitor of cyclin-dependent kinases. 886 73

The cyclin-dependent kinase (Cdk) inhibitor known as p21, which is transcriptionally regulated by p53, can induce G1 arrest when overexpressed and inhibit the kinase activity of a wide variety of cyclin-Cdk complexes. Previous studies have demonstrated that a portion of the conserved region of p21 (amino acids 46-78), which is homologous to similar regions in the related Cdk inhibitors p27 and p57, can bind to Cdk2, and that this region is essential for kinase inhibition. However, the site(s) on Cdk2 that are involved in p21 binding have not been identified. We therefore created mutant Cdk2 molecules with various N-terminal and C-terminal deletions and tested each for their ability to bind to p21 by the yeast two-hybrid and the double-tagging assays. None of the deletion mutants tested bound to p21 by either assay. We next tested whether p21 could bind to Cdk7, a component of the cyclin-activating kinase complex. By both the double-tagging and yeast two-hybrid assays, p21 failed to bind to this protein, consistent with previous reports. However, hybrid molecules consisting of the amino-terminal half of Cdk2 and the carboxy-terminal half of Cdk7 (Cdk2/Cdk7) could bind to p21 by both assays, whereas the Cdk7/Cdk2 hybrids could not. Furthermore, the yeast Cdc28 protein, which is 65% identical with Cdk2, failed to bind to p21 by both the yeast two-hybrid and double-tagging assays. Cdk2/Cdc28 hybrids but not Cdc28/Cdk2 hybrids could bind to p21. These results suggest that the amino-terminal half of Cdk2 is important for p21 binding, consistent with the recently published crystal-lographic data. Our data also suggest that the three-dimensional structure of Cdk2 is likely altered by creating deletion mutants from either the amino- or carboxy-terminal end of the protein. Finally, we have mutated the Cdc28/Cdk2 hybrid protein and isolated several mutants, which are able to bind to p21. This approach may be useful for identifying residues in Cdk2 and Cdc28 that affect their ability to bind to p21 and complement the crystallographic data.
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PMID:The amino terminus of Cdk2 binds p21. 897 68

The connection between cell cycle and cancer has become obvious in as much as it is considered that dysregulated cellular proliferation is a hallmark of cancer. In many studies, the dysregulation of the cyclin-cdk-cki network has been reported in experimental animal and human tumors, but to our knowledge a complete profile of alterations in regulatory molecules in any tumor model system is lacking. In this study, we assessed the expression of various cyclins, cyclin dependent kinases, and cyclin kinase inhibitors in chemically induced squamous papillomas in SENCAR mouse skin. Western blot analysis data showed a significant upregulation of cyclins (31, 6, 19, and 12 folds elevation for cyclin-D1, D2, E, and A, respectively) in tumors compared to the normal skin. The protein expression of the cdk (1, 2, and 4) was also found to be elevated in tumors compared to normal skin (33 fold for cdk1, 14 fold for cdk2, and 9 fold for cdk4). In tumors, compared to the normal skin, a significant increase in the level of protein expression of p27 and p57 (4 and 3 fold, respectively) was evident. In normal skin, p16 and p21 were not detectable but significant expression of these proteins was detected in tumors. Taken together, these data provide evidence that cell cycle deregulation in G1-phase is a critical event during the course of two stage skin carcinogenesis. This may have relevance to epithelial cancers in general.
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PMID:Alterations in cell cycle regulation in mouse skin tumors. 950 Sep 99

The proliferation of cultured astrocytes is positively and negatively regulated, respectively, by the endogenous neuropeptides, endothelin-3 (ET-3) and atrial natriuretic peptide (ANP). Here, we determined the important steps for the modulation by ET and ANP of G1 to S phase cell cycle progression. ET-3 stimulated an increased number of fetal rat diencephalic astrocytes to progress through G1/S, and this was blocked significantly by ANP. ET augmented the gene expression and/or protein production of D-type, A and E cyclins, whereas ANP inhibited these events significantly. ET also stimulated the activation of the cyclin-dependent kinases Cdk2, Cdk4, and Cdk6, directed against the retinoblastoma protein pRb, and this was inhibited by as much as 80% by ANP. As an additional mechanism of cell cycle restraint, ANP stimulated the production of multiple cyclin-dependent kinase inhibitory (CKI) proteins, including p16, p27, and p57. This was critical because antisense oligonucleotides to each CKI reversed ANP-induced inhibition of ET-stimulated DNA synthesis by as much as 85%. CKI antisense oligonucleotides also reversed the ANP inhibition of Cdk phosphorylation of pRb. In turn, ET inhibited ANP-stimulated production of the CKIs, thereby promoting cell cycle progression. Specific and changing associations of the CKI with Cdk2 and Cdk4 were stimulated by ANP and inhibited by ET. Our findings identify several mechanisms by which endogenous modulators of astrocyte proliferation can control the G1-S progression and indicate that multiple CKIs are necessary to restrain cell cycle progression in these cells.
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PMID:Astrocyte progression from G1 to S phase of the cell cycle depends upon multiple protein interaction. 959 46

The suspension of keratinocytes containing episomal forms of the human papillomavirus (HPV)-31 genome in semisolid medium results in the induction of viral late functions. In this study, the suspension in semisolid medium was used to analyze how HPV deregulates the process of cell cycle exit during differentiation. In cells that contain the entire HPV-31 genome, induction of late protein synthesis was found to be linked with the expression of cyclin A. Consistent with analyses in organotypic rafts, the expression of the high-risk E7 oncoprotein alone was sufficient to retain cyclin A expression during suspension-induced differentiation. The cyclin-dependent kinase inhibitors (CKIs) p27 and p57 were found to be up-regulated in normal keratinocytes, as well as in the lines that express the HPV oncoproteins. The up-regulation of these CKIs is coincident with the inhibition of cyclin/cdk activity in normal keratinocytes. Cells expressing E7 were found to retain significant cdk2-associated kinase activity, although it was partially inhibited, coincident with CKI induction. When the phosphorylation state of Rb was examined during differentiation, cells expressing E7 retained phosphorylated forms of Rb, whereas Rb in normal keratinocytes was hypophosphorylated. As previously reported, E7-expressing cells were found to contain less Rb protein than normal keratinocytes. Interestingly, the Rb levels decreased during normal keratinocyte differentiation, and this differentiation-dependent reduction in Rb levels was enhanced by EG and E7 expression. This study identified proteins that may be critical for cell cycle regulation during normal epithelial differentiation and demonstrated that HPV oncoproteins alter their activities.
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PMID:Human papillomavirus oncoproteins alter differentiation-dependent cell cycle exit on suspension in semisolid medium. 977 Apr 16

Differentiation of cells is typically marked by a cessation of proliferation with a concurrent entrance into a distinct metabolic state marked by tissue specific gene expression. The mechanism by which the cell exits the cell cycle in this process is poorly understood. To determine the potential roles of the cell cycle machinery in the regulation of the terminal differentiation process of epidermal cells, we selected a well characterized in vitro model in which primary mouse keratinocytes are induced to differentiate in response to a raised calcium ion concentration in the medium. The withdrawal from the cell cycle correlates very well with a number of changes in the cell cycle machinery. Changes in the phosphorylation status of the Rb family of proteins occurs coordinately with an increased association of p21, p27 and p57 with cdk2. Furthermore, we find that inhibition of cdk2 activity is not sufficient to elicit changes that occur during keratinocyte differentiation. Finally, the previously described v-Ha-ras block of keratinocyte differentiation correlates with altered regulation of both cyclin D1 and cdk2 suggesting that these genes may play a role in the Ha-ras transformation of a keratinocyte.
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PMID:Coordinated changes in cell cycle machinery occur during keratinocyte terminal differentiation. 992 96

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

When renal epithelial cells are exposed to epidermal growth factor-transforming growth factor-beta1 (EGF-TGF-beta1) the typical EGF-mediated hyperplastic growth response is converted to a hypertrophic growth response. Hypertrophy in this setting involves cell entrance into G(1), but arrest of cell cycle progression at the G(1)/S interface. Late G(1) arrest is mediated by retaining retinoblastoma protein (pRB) in its active, hypophosphorylated state. The present studies examine the mechanism by which pRB is retained in its active state. The results demonstrate that TGF-beta1-mediated conversion of hyperplasia to hypertrophy involves preventing activation of cdk2/cyclin E kinase but has no effect on cdk4(6)/cyclin D kinase activity. Preventing activation of cyclin E kinase is associated with 1) decreased abundance of cdk2/cyclin E complexes and 2) retention of p57(Kip2) in formed cdk2/cyclin E complexes. The development of hypertrophy does not involve regulation of either cdk2, cyclin E, or cdc25A protein abundances, or the abundance of p27(Kip1) or p21 in formed complexes.
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PMID:TGF-beta1-mediated hypertrophy involves inhibiting pRB phosphorylation by blocking activation of cyclin E kinase. 1044 72


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