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)

The ubiquitous transcription factor, NF-Y, plays a pivotal role in the cell cycle regulation of the mammalian cyclin A, cdc25C, and cdc2 genes, in the S-phase activation of the ribonucleotide reductase R2 gene, in addition to its critical role as a key proximal promoter factor in the transcriptional regulation of the albumin, collagen, lipoprotein lipase, major histocompatibility complex class II, and a variety of other eukaryotic and viral genes. In this report, the NF-Y complex has been shown to possess histone acetyltransferase activity through physical association with the related histone acetyltransferase enzymes, human GCN5 and P/CAF in vivo. The assembled NF-YA:B:C complex, and the NF-YB:YC, NF-YB:YC (DNA binding-subunit interaction domain), and NF-YC:YB (DNA binding-subunit interaction domain) heterodimers were sufficient to support stable interaction with human GCN5 in vitro, suggesting that these histone acetyltransferases interact with a unique surface in the ancient YB:YC histone-fold motif. Deletion of either N- or C-terminal regions in human GCN5 disrupted interaction with NF-Y in vitro. In addition, human GCN5 was observed to activate NF-Y in transient transfections in vivo using a natural alpha 2(I) collagen promoter. These results suggest that these associated histone acetyltransferases may serve to modulate NF-Y transactivation potential by aiding disruption of local chromatin structure thereby facilitating NF-Y access to its CCAAT box DNA binding sites.
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PMID:NF-Y is associated with the histone acetyltransferases GCN5 and P/CAF. 943 Jun 79

Cyclin-dependent kinases (CDKs) play an important role in the eukaryotic cell cycle progression. Cdc2 (CDK1) is expressed in late G(1)/S phase and required for G(2) to M phase transition in higher eukaryotes. The oncoproteins, SV40 large T antigen and adenovirus E1A, induce a 110-kDa protein which specifically recognizes the two inverted CCAAT motifs of the cdc2 promoter in cycling cells and plays an essential role in transactivation of the human cdc2 promoter. Since these CCAAT motifs also conform to the consensus binding sites for the ubiquitous heterotrimeric transcription factor, CBF/NF-Y, the role of CBF/NF-Y in the transactivation of the cdc2 promoter was examined in this study. Our results indicate that CBF/NF-Y and the 110-kDa protein interact with the CCAAT box motif to form a heteromeric complex. However, mutagenesis of the pentanucleotide CCAAT motif or in the presence of urea greater than 2.5 M, no heteromeric complex was formed. In contrast, the 110-kDa protein could still bind the mutant CCAAT motif or with the wild type motif in the presence of 2.5 M urea. Furthermore, E1A.12S induced the gene expression of all three subunits of CBF/NF-Y. Coexpression of E1A and a dominant negative mutant NF-YA subunit significantly reduced the E1A-mediated transactivation of the cdc2 promoter in a dose-dependent manner. These results support the conclusion that E1A protein mediates optimal transactivation of the human cdc2 promoter by inducing the expression and assembly of a heteromeric complex consisting of the 110-kDa protein and the CBF/NF-Y which interacts with the two CCAAT motifs of the cdc2 promoter.
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PMID:Transactivation of the human cdc2 promoter by adenovirus E1A. E1A induces the expression and assembly of a heteromeric complex consisting of the CCAAT box binding factor, CBF/NF-Y, and a 110-kDa DNA-binding protein. 1043 72

The p53 tumor suppressor protein regulates the transcription of regulatory genes involved in cell cycle arrest and apoptosis. We have reported previously that inducible expression of the p53 gene leads to the cell cycle arrest both at G(1) and G(2)/M in association with induction of p21 and reduction of mitotic cyclins (cyclin A and B) and cdc2 mRNA. In this study, we investigated the mechanism by which p53 regulates transcription of the cdc2 gene. Transient transfection analysis showed that wild type p53 represses whereas various dominant negative mutants of p53 increase cdc2 transcription. The cdc2 promoter activity is not repressed in cells transfected with a transactivation mutant, p53(22/23). An adenovirus oncoprotein, E1B-55K inhibits the p53-mediated repression of the cdc2 promoter, while E1B-19K does not. Since the cdc2 promoter does not contain a TATA sequence, we performed deletion and point mutation analyses and identified the inverted CCAAT sequence located at -76 as a cis-acting element for the p53-mediated regulation. We found that a specific DNA-protein complex is formed at the CCAAT sequence and that this complex contains the NF-Y transcription factor. Consistently, a dominant negative mutant of the NF-YA subunit, NF-YAm29, decreases the cdc2 promoter, and p53 does not further decrease the promoter activity in the presence of NF-YAm29. These results suggest that p53 negatively regulates cdc2 transcription and that the NF-Y transcription factor is required for the p53-mediated regulation.
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PMID:p53 negatively regulates cdc2 transcription via the CCAAT-binding NF-Y transcription factor. 1051 38

NF-Y is composed of three subunits, NF-YA, NF-YB, and NF-YC, all required for DNA binding. All subunits are expressed in proliferating skeletal muscle cells, whereas NF-YA alone is undetectable in terminally differentiated cells in vitro. By immunohistochemistry, we show that the NF-YA protein is not expressed in the nuclei of skeletal and cardiac muscle cells in vivo. By chromatin immunoprecipitation experiments, we demonstrate herein that NF-Y does not bind to the CCAAT boxes of target promoters in differentiated muscle cells. Consistent with this, the activity of these promoters is down-regulated in differentiated muscle cells. Finally, forced expression of the NF-YA protein in cells committed to differentiate leads to an impairment in the down-regulation of cyclin A, cyclin B1, and cdk1 expression and is accompanied by a delay in myogenin expression. Thus, our results indicate that the suppression of NF-Y function is of crucial importance for the inhibition of several cell cycle genes and the induction of the early muscle-specific program in postmitotic muscle cells.
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PMID:Requirement for down-regulation of the CCAAT-binding activity of the NF-Y transcription factor during skeletal muscle differentiation. 1285 58

Cyclins are essential regulators of the cell division cycle. Cyclin B associates with the cyclin-dependent kinase 1 (cdc2) to form a complex which is required for cells to undergo mitosis. In mammalian cells three B-type cyclins have been characterised, cyclin B1, B2 and B3. The cell cycle-dependent synthesis of cyclin B1 and B2 has been investigated in detail displaying maximum expression in G2 which is mainly regulated on the transcriptional level. We have previously shown that this regulation of the mouse cyclin B2 promoter is controlled by a cell cycle-dependent element (CDE) and the cell cycle genes homology region (CHR). Also in a number of other genes CDE/CHR elements repress transcription in G0 and G1 and lead to relief of repression later during the cell cycle. Here, we compare human and mouse cyclin B2 promoters. Both promoters share only nine regions with nucleotide identities. Three of these sites are CCAAT-boxes spaced 33 bp apart which can bind the NF-Y transcriptional activator. NF-Y binding to the human cyclin B2 promoter could be shown by chromatin immunoprecipitation (ChIP) assays. Activation by NF-Y is responsible for more than 93% of the total promoter activity as measured by cotransfecting a plasmid coding for a dominant-negative form of NF-YA. Cell cycle-dependent repression is regulated solely through a CHR. Surprisingly, in contrast to the mouse promoter the CHR in the human cyclin B2 promoter does not rely on a CDE site in tandem with it. Together with the recently described mouse cdc25C promoter, human cyclin B2 is the second identified gene which solely requires a CHR for its cell cycle regulation.
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PMID:Three CCAAT-boxes and a single cell cycle genes homology region (CHR) are the major regulating sites for transcription from the human cyclin B2 promoter. 1290 59

This article investigates the mechanistic aspects of mutant p53 "gain of function" in response to DNA damage. We show that mutant forms of p53 protein interact with NF-Y. The expression of cyclin A, cyclin B1, cdk1, and cdc25C, as well as the cdk1-associated kinase activities, is upregulated after DNA damage, provoking a mutant p53/NF-Y-dependent increase in DNA synthesis. Mutant p53 binds NF-Y target promoters and, upon DNA damage, recruits p300, leading to histone acetylation. The recruitment of mutant p53 to the CCAAT sites is severely impaired upon abrogation of NF-YA expression. Endogenous NF-Y, mutant p53, and p300 proteins form a triple complex upon DNA damage. We demonstrate that aberrant transcriptional regulation underlies the ability of mutant p53 proteins to act as oncogenic factors.
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PMID:Gain of function of mutant p53: the mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. 1695 7

G-protein-coupled receptor-30 (GPR30) shows estrogen-binding affinity and mediates non-genomic signaling of estrogen to regulate cell growth. We here showed for the first time, in contrast to the reported promoting action of GPR30 on the growth of breast and ovarian cancer cells, that activation of GPR30 by the receptor-specific, non-estrogenic ligand G-1 inhibited the growth of androgen-dependent and androgen-independent prostate cancer (PCa) cells in vitro and PC-3 xenografts in vivo. However, G-1 elicited no growth or histological changes in the prostates of intact mice and did not inhibit growth in quiescent BPH-1, an immortalized benign prostatic epithelial cell line. Treatment of PC-3 cells with G-1 induced cell-cycle arrest at the G(2) phase and reduced the expression of G(2)-checkpoint regulators (cyclin-A2, cyclin-B1, cdc25c, and cdc2) and phosphorylation of their common transcriptional regulator NF-YA in PC-3 cells. With extensive use of siRNA-knockdown experiments and the MEK inhibitor PD98059 in this study, we dissected the mechanism underlying G-1-induced inhibition of PC-3 cell growth, which was mediated through GPR30, followed by sustained activation of Erk1/2 and a c-jun/c-fos-dependent upregulation of p21, resulting in the arrest of PC-3 growth at the G(2) phase. The discovery of this signaling pathway lays the foundation for future development of GPR30-based therapies for PCa.
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PMID:Activation of GPR30 inhibits the growth of prostate cancer cells through sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G(2) cell-cycle arrest. 2020 90