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)

Overexpression of cyclin D1 is necessary but by itself insufficient for the development of mantle cell lymphoma (MCL). To identify pathways in the pathogenesis of MCL and the blastoid variant (MLC-BV), we compared the gene-expression profiles of microdissected normal mantle cells, MCL, and MCL-BV by oligonucleotide microarrays and quantitative reverse transcriptase PCR (QRT-PCR). We identified and confirmed the overexpression of several genes in MCL-BV that are involved in the cell cycle control at the G1/S and G2/M checkpoints or inhibit apoptotic cell death. The highly expressed cyclin dependent kinase 4 (CDK4) is a cell cycle kinase that associates with cyclin D1 for the progression through the G1/S checkpoint, whereas overexpression of cdc28 protein kinase 1 (CKS1) blocks the inhibition of the cyclin D1/CDK4 complex by the CDK inhibitor p27/Kip1. Other highly expressed genes in MCL-BV that promote the cells through the G1/S-checkpoint include the oncogenes B-Myb, PIM1, and PIM2, and passage through the G2/M-checkpoint is enhanced by high levels of cdc25B. Furthermore, two highly expressed genes that inhibit apoptosis are defender against cell death (DAD1) and RSK1. In summary, our microarray and QRT-PCR analyses identified several candidate genes whose expression increased when comparing normal follicular mantles with MCL and MCLBV, suggesting a potential pathogenic role in the evolution of MCL-BV.
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PMID:Cell cycle alterations in the blastoid variant of mantle cell lymphoma (MCL-BV) as detected by gene expression profiling of mantle cell lymphoma (MCL) and MCL-BV. 1260 34

The cell cycle-regulated B-Myb transcription factor is required for early embryonic development and is implicated in regulating cell growth and differentiation. In addition to its transcriptional regulatory properties, recent data indicate that B-Myb can release active cyclin/Cdk2 activity from the retinoblastoma-related p107 protein by directly interacting with the p107 N terminus. As this p107 domain has homology to the cyclin-binding domains of the p21(Waf1/Cip1) family of cyclin-dependent kinase inhibitors (CKIs), we investigated in this study whether B-Myb could also interact with these CKIs. No in vivo interaction was found with either p21(Waf1/Cip1) or p27(KIP1), however, binding to p57(KIP2) was readily detectable in both in vivo and in vitro assays. The B-Myb-interacting region of p57(KIP2) mapped to the cyclin-binding domain. Consistent with this, B-Myb competed with cyclin A2 for binding to p57(KIP2), resulting in release of active cyclin/Cdk2 kinase. Moreover, B-Myb partially overcame the ability of p57(KIP2) to induce G1 arrest in Saos-2 cells. Despite similarities with previous p107 studies, the B-Myb domains required for interaction with p57(KIP2) were quite different from those implicated for p107. Thus, it is evident that B-Myb may promote cell proliferation by a non-transcriptional mechanism that involves release of active cyclin/Cdk2 from p57(KIP2) as well as p107.
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PMID:The cell cycle-regulated B-Myb transcription factor overcomes cyclin-dependent kinase inhibitory activity of p57(KIP2) by interacting with its cyclin-binding domain. 1294 99

The expression of genes required for progression through the cell cycle is highly modulated through a regulatory axis containing the E2F transcription factor and retinoblastoma tumour suppressor protein families. One of the genes regulated through this mechanism encodes the B-Myb transcription factor, which has been shown to be critically required for early embryonal development in the mouse. Transcriptional activity of B-Myb is substantially enhanced in S phase through modification by cyclin A/cdk2, and the evidence points squarely to the major role being played by B-Myb during this phase of the cell cycle. We discuss in this review recent findings suggesting that B-Myb is a multifunctional protein that has, in addition to its transcriptional properties, the ability to interact directly with other regulators of the cell cycle.
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PMID:Cell cycle regulation by the B-Myb transcription factor. 1462 84

B-Myb is a highly conserved member of the Myb family of transcription factors whose activity is regulated during the cell cycle. Previous work has shown that the activity of B-Myb is stimulated by cyclin A/Cdk2-dependent phosphorylation whereas interaction of B-Myb with cyclin D1 inhibits its activity. Here, we have investigated the role of p300 as a coactivator for B-Myb. We show that B-Myb-dependent transactivation is stimulated by p300 as a result of interaction between B-Myb and p300. We have mapped the sequences responsible for the interaction of B-Myb and p300 to the E1A-binding region of p300 and the transactivation domain of B-Myb, respectively. Furthermore, our data suggest that phosphorylation of B-Myb stimulates its acetylation by p300 and that the acetylation of B-Myb is necessary for the full stimulation of its transactivation potential by p300. We have also studied the effect of cyclin D1 on the cooperation of B-Myb and p300. Based on our results we propose that cyclin D1 inhibits the activity of B-Myb by interfering with the interaction of B-Myb and p300. The data reported here provide novel insight into the mechanisms by which the activity of B-Myb is regulated during the cell cycle. Taken together they suggest that the coactivator p300 plays an important role in this regulation and that the cooperation of B-Myb and p300 is orchestrated by cyclins A and D1.
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PMID:The cooperation of B-Myb with the coactivator p300 is orchestrated by cyclins A and D1. 1497 51

Previous work has provided evidence for E2F-dependent transcription control of both G1/S- and G2/M-regulated genes. Analysis of the G2-regulated cdc2 and cyclin B1 genes reveals the presence of both positive- and negative-acting E2F promoter elements. Additional elements provide both positive (CCAAT and Myb) and negative (CHR) control. Chromatin immunoprecipitation assays identify multiple interactions of E2F proteins that include those previously shown to activate and repress transcription. We find that E2F1, E2F2, and E2F3 bind to the positive-acting E2F site in the cdc2 promoter, whereas E2F4 binds to the negative-acting site. We also find that binding of an activator E2F is dependent on an adjacent CCAAT site that is bound by the NF-Y transcription factor and binding of a repressor E2F is dependent on an adjacent CHR element, suggesting a role for cooperative interactions in determining both activation and repression. Finally, the kinetics of B-Myb interaction with the G2-regulated promoters coincides with the activation of the genes, and RNAi-mediated reduction of B-Myb inhibits expression of cyclin B1 and cdc2. The ability of B-Myb to interact with the cdc2 promoter is dependent on an intact E2F binding site. These results thus point to a role for E2Fs, together with B-Myb, which is an E2F-regulated gene expressed at G1/S, in linking the regulation of genes at G1/S and G2/M.
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PMID:E2Fs link the control of G1/S and G2/M transcription. 1551 Feb 13

B-Myb represses collagen gene transcription in vascular smooth muscle cells (SMCs) in vitro and in vivo. Here we sought to determine whether elastin is similarly repressed by B-Myb. Levels of tropoelastin mRNA and protein were lower in aortas and isolated SMCs of adult transgenic mice expressing the human B-myb gene, driven by the basal cytomegalovirus promoter, compared with age-matched wild type (WT) animals. However, the vessel wall architecture and levels of insoluble elastin revealed no differences. Since elastin deposition occurs early in development, microarray analysis was performed using nontransgenic mice. Aortic levels of tropoelastin mRNA were low during embryonal growth and increased substantially in neonates, whereas B-myb levels varied inversely. Tropoelastin mRNA expression in aortas of 6-day-old neonatal transgenic and WT animals was comparable. Recently, we demonstrated that cyclin A-Cdk2 prevents B-Myb-mediated repression of collagen promoter activity. Cyclin A2 levels were higher in neonatal versus adult WT or transgenic mouse aortas. Ectopic cyclin A expression reversed the ability of B-Myb to repress elastin gene promoter activity in adult SMCs. These results demonstrate for the first time that B-Myb represses SMC elastin gene expression and that cyclin A plays a role in the developmental regulation of elastin gene expression in the aorta. Furthermore, the findings provide additional insight into the mechanism of B-myb-mediated resistance to femoral artery injury.
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PMID:B-Myb represses elastin gene expression in aortic smooth muscle cells. 1561 10

B-Myb is a highly conserved member of the Myb family of transcription factors which plays an important role during the cell cycle. Previous work has shown that B-Myb is phosphorylated at several sites by cyclin A/Cdk2 in the early S-phase. These phosphorylations increase the transactivation potential of B-Myb by counteracting the repressive function of an inhibitory domain located at the carboxyl-terminus of B-Myb. As yet, only a few genes have been identified as B-Myb target genes. Previous work has suggested that the cyclin D1 gene might be regulated by B-Myb. Here, we have studied the effect of B-Myb on the promoter of the cyclin D1 gene. We show that B-Myb is a potent activator of the cyclin D1 promoter and that this activation is not mediated by Myb binding sites but rather by a group of Sp1 binding sites which have previously been shown to be crucial for cyclin D1 promoter activity. Our data show that the C-terminal domain of B-Myb is required for the activation of the cyclin D1 promoter and that this part of B-Myb interacts with Sp1. Finally, we have found that the promoter of the cyclin A1 gene is also activated by B-Myb by a Sp1 binding site-dependent mechanism. The effect of B-Myb on the promoters of the cyclin A1 and D1 genes is reminiscent of the mechanism that has been proposed for the autoregulation of the B-myb promoter by B-Myb, which also involves Sp1 binding sites. Taken together, our identification of two novel B-Myb responsive promoters whose activation by B-Myb does not involve Myb binding sites extends previous evidence for the existence of a distinct mechanism of transactivation by B-Myb which is dependent on Sp1 binding sites. The observation that this mechanism is not subject to the inhibitory effect of the C-terminal domain of B-Myb but rather requires this domain supports the notion that the Sp1 site-dependent mechanism is already active in the G1-phase prior to the phosphorylation of B-Myb by cyclin A/Cdk2.
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PMID:Regulation of the cyclin D1 and cyclin A1 promoters by B-Myb is mediated by Sp1 binding sites. 1592 73

The high-risk human papillomavirus (HPV) E7 oncogene abrogates DNA damage-induced G1 checkpoint but the mechanism is not fully understood. The G1 kinase Cdk2 is activated in E7-expressing cells. However, whether Cdk2 is required for E7 to abrogate the G1 checkpoint is not known. Accumulating evidence implicates a role for the mitotic Cdk1 in G1/S phase transition in the absence of Cdk2. We therefore examined the expression and requirement of Cdk1 and Cdk2 in the G1 checkpoint abrogation in E7-expressing cells. Although both Cdk1 and Cdk2 were up-regulated in E7-expressing cells upon DNA damage, down-regulation of Cdk1 but not Cdk2 impairs the ability of E7 to abrogate the G1 checkpoint. Our study thus demonstrated an important role for Cdk1 in bypassing the G1 checkpoint in E7-expressing cells. To understand the mechanism by which E7 activates Cdk1, we examined the transcription factor B-Myb. Our studies demonstrated that downregulation of B-Myb reduced the steady-state level of Cdk1 and induced G1 arrest in E7-expressing cells upon DNA damage. In addition, it remains a mystery how E7 promotes cell cycle progression in the presence of Cdk inhibitor p21. As p21 binds Cdk1 with lower affinity than Cdk2, our results suggest a mechanism by which E7 bypasses the inhibitory effect of p21. Nonetheless, our studies demonstrated that p21 still possessed partial ability to arrest cells at G1 phase in E7-expressing cells. These studies shed light on mechanisms by which HPV E7 modulates cell cycle checkpoint.
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PMID:Role of Cdk1 in DNA damage-induced G1 checkpoint abrogation by the human papillomavirus E7 oncogene. 2548 5


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