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)

Regulation of gene expression in mammals through methylation of cytosine residues at CpG dinucleotides is involved in the development and progression of tumors. Because many genes that are involved in the control of cell proliferation are regulated by members of the E2F family of transcription factors and because some E2F DNA-binding sites are methylated in vivo, we have investigated whether CpG methylation can regulate E2F functions. We show here that methylation of E2F elements derived from the dihydrofolate reductase, E2F1, and cdc2 promoters prevents the binding of all E2F family members tested (E2F1 through E2F5). In contrast, methylation of the E2F elements derived from the c-myc and c-myb promoters minimally affects the binding of E2F2, E2F3, E2F4, and E2F5 but significantly inhibits the binding of E2F1. Consistent with these studies, E2F3, but not E2F1, activates transcription through methylated E2F sites derived from the c-myb and c-myc genes whereas both E2F1 and E2F3 fail to transactivate a reporter gene that is under the control of a methylated dihydrofolate reductase E2F site. Together, these data illustrate a means through which E2F activity can be controlled.
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PMID:CpG methylation as a mechanism for the regulation of E2F activity. 1082 96

Spinal cord injury causes secondary biochemical changes leading to neuronal cell death. To clarify the molecular basis of this delayed injury, we subjected rats to spinal cord injury and identified gene expression patterns by high-density oligonucleotide arrays (8,800 genes studied) at 30 minutes, 4 hours, 24 hours, or 7 days after injury (total of 26 U34A profiles). Detailed analyses were limited to 4,300 genes consistently expressed above background. Temporal clustering showed rapid expression of immediate early genes (30 minutes), followed by genes associated with inflammation, oxidative stress, DNA damage, and cell cycle (4 and 24 hours). Functional clustering showed a novel pattern of cell cycle mRNAs at 4 and 24 hours after trauma. Quantitative reverse transcription polymerase chain reaction verified mRNA changes in this group, which included gadd45a, c-myc, cyclin D1 and cdk4, pcna, cyclin G, Rb, and E2F5. Changes in their protein products were quantified by Western blot, and cell-specific expression was determined by immunocytochemistry. Cell cycle proteins showed an increased expression 24 hours after injury and were, in part, colocalized in neurons showing morphological evidence of apoptosis. These findings suggest that cell cycle-related genes, induced after spinal cord injury, are involved in neuronal damage and subsequent cell death.
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PMID:Gene profiling in spinal cord injury shows role of cell cycle in neuronal death. 1266 13

The E2F family of transcription factors regulate the expression of many growth-related genes in a cell cycle-dependent manner. These transcription factors can activate or, in conjunction with an Rb-related protein, repress transcription. E2F transcriptional activity is regulated at several different levels that are each linked to cell cycle progression. In many cell types, E2F4 and E2F5 are the predominant E2F species during G(0) and early G(1) and function primarily as repressors of E2F-regulated genes. In this study, co-immunoprecipitation techniques were used to demonstrate that cyclins D1, D2, and D3 are capable of interacting with E2F4, E2F5, and DP1. Overexpression of cyclin D1/cdk4 reduced E2F4-mediated transcription in a simple reporter gene assay and electrophoretic mobility shift analyses using nuclear extracts from transfected cells indicated that cyclin D1/cdk4 disrupts the DNA-binding ability of E2F4. Cell cycle analysis following stimulation of serum-starved 3T3 cells indicated that E2F4 undergoes changes in its phosphorylation pattern coincident with the synthesis of cyclin D1. Examination of a series of E2F4 deletion mutants indicated that a cyclin D1-binding site located close to the carboxyl terminus of E2F4 was critical for the disruption of DNA binding by cyclin D1/cdk4. These data support a model in which E2F4 DNA binding is abolished during mid-G(1) at the same time when E2F interactions with pRb-related proteins are disrupted by cyclin D1/cdk4.
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PMID:Cyclin D1/cdk4 can interact with E2F4/DP1 and disrupts its DNA-binding capacity. 1789 19

The papillomavirus life cycle is intimately coupled to the differentiation state of the infected epithelium. Since papillomaviruses lack most of the rate-limiting enzymes required for genome synthesis, they need to uncouple keratinocyte differentiation from cell cycle arrest and maintain or reestablish a replication-competent state within terminally differentiated keratinocytes. The human papillomavirus (HPV) E7 protein appears to be a major determinant for this activity and induces aberrant S-phase entry through the inactivation of the retinoblastoma tumor suppressor and related pocket proteins. In addition, E7 can abrogate p21 and p27. Together, this leads to the activation of E2F1 to E2F5, enhanced expression of E2F-responsive genes, and increased cdk2 activity. E2F6 is a pRB-independent, noncanonical member of the E2F transcription factor family that acts as a transcriptional repressor. E2F6 expression is activated in S phase through an E2F-dependent mechanism and thus may provide a negative-feedback mechanism that slows down S-phase progression and/or exit in response to the activation of the other E2F transcription factors. Here, we show that low- and high-risk HPV E7 proteins, as well as simian virus 40 T antigen and adenovirus E1A, can associate with and inactivate the transcriptional repression activity of E2F6, thereby subverting a critical cellular defense mechanism. This may result in the extended S-phase competence of HPV-infected cells. E2F6 is a component of polycomb group complexes, which bind to silenced chromatin and are critical for the maintenance of cell fate. We show that E7-expressing cells show decreased staining for E2F6/polycomb complexes and that this is at least in part dependent on the association with E2F6.
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PMID:Human papillomavirus type 16 E7 oncoprotein associates with E2F6. 1857 89