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)

In the axial elements of synaptonemal complexes (SCs) of the rat, major protein components have been identified, with relative electrophoretic mobilities (M rs) of 30 000-33 000 and 190 000. Using monoclonal anti-SC antibodies, we isolated cDNA fragments which encode the 190 000 M r component of rat SCs. The translation product predicted from the nucleotide sequence of the cDNA, called SCP2 (for synaptonemal complex protein 2), is a basic protein (pI = 8.0) with a molecular mass of 173 kDa. At the C-terminus, a stretch of approximately 50 amino acid residues is predicted to be capable of forming coiled-coil structures. SCP2 contains two clusters of S/T-P motifs, which are common in DNA-binding proteins. These clusters flank the central, most basic part of the protein (pI = 9.5). Three of the S/T-P motifs are potential target sites for p34(cdc2) protein kinase. In addition, SCP2 has eight potential cAMP/cGMP-dependent protein kinase target sites. The gene encoding SCP2 is transcribed specifically in the testis, in meiotic prophase cells. At the amino acid sequence and secondary structural level, SCP2 shows some similarity to the Red1 protein, which is involved in meiotic recombination and the assembly of axial elements of SCs in yeast. We speculate that SCP2 is a DNA-binding protein involved in the structural organization of meiotic prophase chromosomes.
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PMID:SCP2: a major protein component of the axial elements of synaptonemal complexes of the rat. 959 39

Parasitic protozoa infecting humans have a staggering impact on public health, especially in the developing world. Furthermore, several protozoan species are major pathogens of domestic animals and have a considerable impact on food production. In many instances, the parasites have developed resistance against available chemotherapeutic agents, making the search for alternative drugs a priority. In line with the current interest in protein kinases inhibitors as potential drugs against a variety of diseases, the possibility that protein kinases may represent targets for novel anti-parasitic agents is being explored. Research into parasite protein kinases has benefited greatly from genome and EST sequencing projects, with the genomes of a few species fully sequenced (notably that of the human malaria parasite Plasmodium falciparum) and several more under way. The overall picture that emerged from research in this area shows that the phylogenetic isolation of parasitic protozoa is reflected by atypical structural and functional properties of many of their protein kinase homologues. Likewise, evidence is emerging, which suggests that the organisation of some otherwise well-conserved signal transduction pathways is divergent in some parasitic species. The differences between protein kinases of a parasite and their homologues in its host cell suggest that specific inhibition of the former can be achieved. The development of anti-parasitic drugs based on protein kinase inhibition is being pursued following two avenues: one consists of screening chemical libraries on recombinant enzymes; several protein kinases from parasitic protozoa are now available for this approach. The second approach relies on the identification of the molecular targets of kinase inhibitors which display anti-parasitic properties. This has led to promising developments in a few instances, in particular regarding PKG as a drug target against Eimeria and Toxoplasma, and purvalanol B, a purine-based CDK inhibitor which appears to affect unexpected targets in several protozoan parasites. The recent resolution of the structure of a Plasmodium protein kinase complexed with small inhibitory molecules opens the way to a rational approach towards the design of anti-parasitic drugs based on kinase inhibition.
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PMID:Protein kinases as targets for anti-parasitic chemotherapy. 1502 58

Renal interstitial fibrosis is believed to play a key role in the development of diabetic nephropathy (DN), and advanced glycation end-products (AGE) may contribute importantly to this. Recent reports have shown that nitric oxide (NO) is closely linked to the renal interstitial fibrosis of DN. In this study, the mechanisms by which NO and its downstream signals mediate the AGE-induced proliferative response in normal rat kidney fibroblasts (NRK-49F) are examined. AGE decreased NO production, cyclic guanosine 5'monophosphate (cGMP) synthesis, and cGMP-dependent protein kinase (PKG) activation time- and dose-dependently. These effects were not observed when cells were treated with nonglycated BSA. NO and inducible nitric oxide synthase (iNOS) stimulated by NO donors S-nitroso-N-acetylpenicillamine (SNAP)/sodium nitroprusside (SNP) and PKG activator 8-para-chlorophenylthio-cGMP (8-pCPT-cGMP) prevented both AGE-induced proliferation and Janus kinase 2 (JAK2)-signal transducers and activators of transcription 5 (STAT5) activation but not p42/p44 mitogen-activated protein kinase (MAPK) activation. The ability of NO-PKG to inhibit AGE-induced cell cycle progression was verified by the observation that SNAP, SNP, and 8-pCPT-cGMP inhibited both cyclin D1 and cdk4 activation. Furthermore, induction of NO-PKG significantly increased p21Waf1/Cip1 expression in AGE-treated NRK-49F cells. The data suggest that the NO-PKG pathway inhibits AGE-induced proliferation by suppressing activation of JAK2-STAT5 and cyclin D1/cdk4 and induction of p21Waf1/Cip1.
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PMID:Effect of nitric oxide-cGMP-dependent protein kinase activation on advanced glycation end-product-induced proliferation in renal fibroblasts. 1595 24

Nitric oxide (NO) has been suggested to be associated with tubulointerstitial fibrosis in diabetic nephropathy. Abnormal glucose handling in the tubulointerstitium may play an important role in the development of diabetic nephropathy. This study was designed to investigate the effect of NO generation and action in renal fibroblasts exposed to high glucose (HG). We found that HG (500 mg/dl) significantly decreased nitrite production compared with normal glucose (100 mg/dl) when the incubation period was for 12, 18, or 24 h. HG inhibited cGMP-dependent protein kinase (PKG) activation at 4, 8, and 12 h. Both NO donors and PKG activator treatment induced high levels of NO, inducible nitric oxide synthase, and PKG in HG-incubated cells. Interestingly, HG-induced Janus kinase 2-signal transducers and activators of transcription 1 (STAT1) activation but not STAT3 or STAT5 activation at 30 min were blocked by NO donors and PKG activator. Moreover, HG-enhanced Raf-1 and p42/p44 MAPK phosphorylation were markedly suppressed by NO donors or PKG activator. The ability of NO-PKG to inhibit HG-induced cell cycle progression was verified by the observation that NO donors and PKG activator inhibited cdk4 activation and increased p21(Waf1/Cip1) and p16(INK4a) (but not p27(Kip1)) expression in HG-treated renal fibroblasts. Collectively, these data suggest that HG significantly blunted NO signaling, and activation of the NO-PKG pathway may modulate HG-enhanced mitogenic response via specific pathways.
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PMID:Role of nitric oxide in high glucose-induced mitogenic response in renal fibroblasts. 1676 78

Protein kinases play important roles in regulating cellular signal transduction and other biochemical processes, and they are attractive targets for drug discovery programs in many disease areas. Most kinase inhibitors under development as drugs act by directly competing with ATP at the ATP-binding site of the kinase. There are more than 500 protein kinases, and the ATP-binding site is highly conserved among them. Therefore selectivity is an essential requirement for clinically effective drugs, and understanding the structural characteristics of ATP-binding sites is of crucial importance. The objective of the present study was to elucidate the structural characteristics of the adenosine-binding site of four major kinase groups, AGC (PKA, PKG, and PKC families), CaMK (calcium/calmodulin-dependent protein kinases), CMGC (CDK, MAPK, GSK3, and CLK families), and TK (tyrosine kinases). To do this, we classified the kinases into groups by using feed-forward multilayer perceptron (MLP) neural networks and structural, electronic, and hydrophobic descriptors of the amino acids at the adenosine-binding site. A total of 275 kinases were classified in two ways: (1) kinases belonging to a certain group were distinguished from those not belonging to that group, and (2) all of the kinases were classified into four groups. More than 85% of the kinases were correctly classified by both methods. Trained neural networks clarified which amino acids and which properties characterize the adenosine-binding site of each group, and the results were visualized by molecular graphics. Comparison of the modeled neural networks and the distributions of amino acids provided more detailed information on the structural characteristics of each group. Application of the present results to drug development is also discussed.
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PMID:Elucidation of characteristic structural features of ligand binding sites of protein kinases: a neural network approach. 1699 46

Toxoplasma gondii is an important opportunistic parasite that infects almost all warm-blooded animals, causing congenital neurological and ocular diseases, especially in immunocompromised humans. The available therapeutic drugs are hypersensitive and toxic, and no vaccine is available to block the transmission of this parasite. Safer and more effective drugs are thus urgently needed to treat toxoplasmosis. Protein kinases (PKs) play crucial roles in the proliferation, differentiation, and pathogenesis of T. gondii. T. gondii calcium-dependent protein kinase 1 and cGMP-dependent protein kinase are associated with cell invasion; mitogen-activated protein kinase 1 and cAMP-dependent protein kinase are involved in stress response and conversion from tachyzoite to bradyzoite; casein kinase 1 and cdc2 cyclin-dependent kinase control cell cycle. Rhoptry kinases, the T. gondii-specific PKs, are involved in host manipulation. Because of their difference in structure and function from that of mammalian PKs, T. gondii PKs are promising drug targets. In this review, we describe the functions of T. gondii protein kinases and their inhibitors as potential drugs against T. gondii.
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PMID:Protein kinases of Toxoplasma gondii: functions and drug targets. 2368 Nov 93

HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) kills tumor cells broadly suggesting that conserved survival pathways are perturbed. We now identify nucleotide-binding proteins as HAMLET binding partners, accounting for about 35% of all HAMLET targets in a protein microarray comprising 8000 human proteins. Target kinases were present in all branches of the Kinome tree, including 26 tyrosine kinases, 10 tyrosine kinase-like kinases, 13 homologs of yeast sterile kinases, 4 casein kinase 1 kinases, 15 containing PKA, PKG, PKC family kinases, 15 calcium/calmodulin-dependent protein kinase kinases and 13 kinases from CDK, MAPK, GSK3, CLK families. HAMLET acted as a broad kinase inhibitor in vitro, as defined in a screen of 347 wild-type, 93 mutant, 19 atypical and 17 lipid kinases. Inhibition of phosphorylation was also detected in extracts from HAMLET-treated lung carcinoma cells. In addition, HAMLET recognized 24 Ras family proteins and bound to Ras, RasL11B and Rap1B on the cytoplasmic face of the plasma membrane. Direct cellular interactions between HAMLET and activated Ras family members including Braf were confirmed by co-immunoprecipitation. As a consequence, oncogenic Ras and Braf activity was inhibited and HAMLET and Braf inhibitors synergistically increased tumor cell death in response to HAMLET. Unlike most small molecule kinase inhibitors, HAMLET showed selectivity for tumor cells in vitro and in vivo. The results identify nucleotide-binding proteins as HAMLET targets and suggest that dysregulation of the ATPase/kinase/GTPase machinery contributes to cell death, following the initial, selective recognition of HAMLET by tumor cells. The findings thus provide a molecular basis for the conserved tumoricidal effect of HAMLET, through dysregulation of kinases and oncogenic GTPases, to which tumor cells are addicted.
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PMID:Targeting of nucleotide-binding proteins by HAMLET--a conserved tumor cell death mechanism. 2602 28

To gain insights into differences in the virulence among T. gondii strains at the post-translational level, we conducted a quantitative analysis of the phosphoproteome profile of T. gondii strains belonging to three different genotypes. Phosphopeptides from three strains, type I (RH strain), type II (PRU strain) and ToxoDB#9 (PYS strain), were enriched by titanium dioxide (TiO2) affinity chromatography and quantified using iTRAQ technology. A total of 1,441 phosphopeptides, 1,250 phosphorylation sites and 759 phosphoproteins were detected. In addition, 392, 298, and 436 differentially expressed phosphoproteins (DEPs) were identified in RH strain when comparing RH/PRU strains, in PRU strain when comparing PRU/PYS strains, and in PYS strain when comparing PYS/RH strains, respectively. Functional characterization of the DEPs using GO, KEGG, and STRING analyses revealed marked differences between the three strains. In silico kinase substrate motif analysis of the DEPs revealed three (RxxS, SxxE, and SxxxE), three (RxxS, SxxE, and SP), and five (SxxE, SP, SxE, LxRxxS, and RxxS) motifs in RH strain when comparing RH/PRU strains, in PRU strain when comparing PRU/PYS, and in PYS strain when comparing PYS/RH strains, respectively. This suggests that multiple overrepresented protein kinases including PKA, PKG, CKII, IKK, and MAPK could be involved in such a difference between T. gondii strains. Kinase associated network analysis showed that ROP5, ROP16, and cell-cycle-associated protein kinase CDK were the most connected kinase peptides. Our data reveal significant changes in the abundance of phosphoproteins between T. gondii genotypes, which explain some of the mechanisms that contribute to the virulence heterogeneity of this parasite.
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PMID:iTRAQ-Based Global Phosphoproteomics Reveals Novel Molecular Differences Between Toxoplasma gondii Strains of Different Genotypes. 3150 80