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)

7-Hydroxystaurosporine (UCN-01) is a potent inhibitor of protein kinase C (PKC) isozymes alpha, beta, and gamma [Seynaeve et al., Mol. Pharmacol, 45: 1207-1214, 1994] that also has antitumor effects in vivo. To determine whether inhibition of PKC can be related to inhibition of cell growth with induction of apoptosis, we compared the effects of UCN-01 to those of the highly selective bisindolylmaleimide PKC antagonist GF 109203X in leukemic T-cell lines. Both compounds potently inhibited PKC activity when added to T-cell membrane preparations and reversed phorbol ester-induced c-fos gene expression in intact cells. However, whereas UCN-01 potently inhibited growth of Jurkat, Molt-3, Molt-4, and Hut-78 cells (IC50 = 20-65 nM, irreversible after 24 h of exposure), GF 109203X had IC50s for cell growth of 3.6-5.0 muM. Less than 3 h after addition, UCN-01 but not GF 109203X-treated cells displayed loss of cells with G2-M DNA content, appearance of a hypodiploid DNA fraction, and evidence of internucleosomal DNA fragmentation. Six h after treatment, cells appeared to accumulate with S-phase DNA content. These effects correlated with selective UCN-01 but not GF 109203X-induced decrease in total and tyrosine phosphorylation of cyclin-dependent kinases (cdks) 1 and 2, and with increases in the histone H1 kinase activities of cdk1 and cdk2. UCN-01 was relatively less potent in inhibition of properly activated cdk1 and cdk2 when added in vitro to H1 kinase assays (IC50 = 1000 and 600 nM, respectively). We conclude that inhibition of PKC alone is not sufficient to account for the actions of UCN-01 and are led to the hypothesis that inappropriate cdk activation either correlates with or actually mediates cell growth inhibition with apoptosis in T lymphoblasts exposed to UCN-01.
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PMID:Apoptosis in 7-hydroxystaurosporine-treated T lymphoblasts correlates with activation of cyclin-dependent kinases 1 and 2. 854 21

A 20-kDa DNA-binding protein that binds the AT-rich sequences within the promoters of the brain-specific protein kinase C (PKC) gamma and neurogranin/RC3 genes has been characterized as chromosomal nonhistone high-mobility-group protein (HMG)-I. This protein is a substrate of PKC alpha, beta, gamma, and delta but is poorly phosphorylated by PKC epsilon and zeta. Two major (Ser44 and Ser64) and four minor phosphorylation sites have been identified. The extents of phosphorylation of Ser44 and Ser64 were 1:1, whereas those of the four minor sites all together were <30% of the major one. These PKC phosphorylation sites are distinct from those phosphorylated by cdc2 kinase, which phosphorylates Thr53 and Thr78. Phosphorylation of HMG-I by PKC resulted in a reduction of DNA-binding affinity by 28-fold as compared with 12-fold caused by the phosphorylation with cdc2 kinase. HMG-I could be additively phosphorylated by cdc2 kinase and PKC, and the resulting doubly phosphorylated protein exhibited a >100-fold reduction in binding affinity. The two cdc2 kinase phosphorylation sites of HMG-I are adjacent to the N terminus of two of the three predicted DNA-binding domains. In comparison, one of the major PKC phosphorylation sites, Ser64, is adjacent to the C terminus of the second DNA-binding domain, whereas Ser44 is located within the spanning region between the first and second DNA-binding domains. The current results suggest that phosphorylation of the mammalian HMG-I by PKC alone or in combination with cdc2 kinase provides an effective mechanism for the regulation of HMG-I function.
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PMID:Phosphorylation of HMG-I by protein kinase C attenuates its binding affinity to the promoter regions of protein kinase C gamma and neurogranin/RC3 genes. 1061 44

All-trans retinoic acid (ATRA) can down regulate the anti-apoptotic protein Bcl-2 and the cell cycle proteins cyclin D1 and cdk2 in estrogen receptor-positive breast cancer cells. We show here that retinoids can also reduce expression of the inhibitor of apoptosis protein, survivin. Here we have compared the regulation of these proteins in MCF-7 and ZR-75 breast cancer cells by natural and synthetic retinoids selective for the RA receptors (RARs) alpha, beta, and gamma then correlated these with growth inhibition, induction of apoptosis and chemosensitization to Taxol. In both cell lines ATRA and 9-cis RA induced the most profound decreases in cyclin D1 and cdk2 expression and also mediated the largest growth inhibition. The RARalpha agonist, Ro 40-6055 also strongly downregulated these proteins although did not produce an equivalent decrease in S-phase cells. Only ATRA induced RARbeta expression. ATRA, 9-cis RA and 4-HPR initiated the highest level of apoptosis as determined by mitochondrial Bax translocation, while only ATRA and 9-cis RA strongly reduced Bcl-2 and survivin protein expression. Enumeration of dead cells over 96 h correlated well with downregulation of both survivin and Bcl-2. Simultaneous retinoid-mediated reduction of both these proteins also predicted optimal Taxol sensitization. 4-HPR was much weaker than the natural retinoids with respect to Taxol sensitization, consistent with the proposed requirement for reduced Bcl-2 in this synergy. Neither the extent of cell cycle protein regulation nor AP-1 inhibition fully predicted the antiproliferative effect of the synthetic retinoids suggesting that growth inhibition requires regulation of a spectrum of RAR-regulated gene products in addition even to pivotal cell cycle proteins.
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PMID:Differential regulation of protein expression, growth and apoptosis by natural and synthetic retinoids. 1458 26

The RNA-binding protein CUGBP1 regulates translation of proteins in a variety of biological processes. In this study, we show that aging liver increases CUGBP1 translational activities by induction of a high molecular weight protein-protein complex of CUGBP1. The complex contains CUGBP1, subunits alpha, beta, and gamma of the initiation translation factor eIF2, and four proteins of the endoplasmic reticulum, eR90, CRT, eR60, and Grp78. The induction of the CUGBP1-eIF2 complex in old livers is associated with the elevation of protein levels of CUGBP1 and with the hyper-phosphorylation of CUGBP1 by a cyclin D3-cdk4 kinase, activity of which is increased with age. We have examined the role of the elevation of CUGBP1 and the role of cyclin D3-cdk4-mediated phosphorylation of CUGBP1 in the formation of the CUGBP1-eIF2 complex by using CUGBP1 transgenic mice and young animals expressing high levels of cyclin D3 after injection with cyclin D3 plasmid. These studies showed that both the increased levels of CUGBP1 and cdk4-mediated hyper-phosphorylation of CUGBP1 are involved in the age-associated induction of the CUGBP1-eIF2 complex. The CUGBP1-eIF2 complex is bound to C/EBPbeta mRNA in the liver of old animals, and this binding correlates with the increased amounts of liver-enriched activator protein and liver-enriched inhibitory protein. Consistent with these observations, the purified CUGBP1-eIF2 complex binds to the 5' region of C/EBPbeta mRNA and significantly increases translation of the three isoforms of C/EBPbeta in a cell-free translation system, in cultured cells, and in the liver. Thus, these studies demonstrated that age-mediated induction of the CUGBP1-eIF2 complex changes translation of C/EBPbeta in old livers.
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PMID:Age-specific CUGBP1-eIF2 complex increases translation of CCAAT/enhancer-binding protein beta in old liver. 1693 14

ICP22 is a multifunctional herpes simplex virus 1 (HSV-1) regulatory protein that regulates the accumulation of a subset of late (gamma(2)) proteins exemplified by U(L)38, U(L)41, and U(S)11. ICP22 binds the cyclin-dependent kinase 9 (cdk9) but not cdk7, and this complex in conjunction with viral protein kinases phosphorylates the carboxyl terminus of RNA polymerase II (Pol II) in vitro. The primary function of cdk9 and its partners, the cyclin T variants, is in the elongation of RNA transcripts, although functions related to the initiation and processing of transcripts have also been reported. We report two series of experiments designed to probe the role of cdk9 in infected cells. In the first, infected cells were treated with 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole (DRB), a specific inhibitor of cdk9. In cells treated with DRB, the major effect was in the accumulation of viral RNAs and proteins regulated by ICP22. The accumulation of alpha, beta, or gamma proteins not regulated by ICP22 was not affected by the drug. The results obtained with DRB were duplicated in cells transfected with small interfering RNA (siRNA) targeting cdk9 mRNAs. Interestingly, DRB and siRNA reduced the levels of ICP22 but not those of other alpha gene products. In addition, cdk9 and ICP22 appeared to colocalize with RNA Pol II in wild-type-virus-infected cells but not in DeltaU(L)13-infected cells. We conclude that cdk9 plays a critical role in the optimization of expression of genes regulated by ICP22 and that one function of cdk9 in HSV-1-infected cells may be to bring ICP22 into the RNA Pol II transcriptional complex.
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PMID:Role of cdk9 in the optimization of expression of the genes regulated by ICP22 of herpes simplex virus 1. 1875 2