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)

Using dephosphorylated neurofilament (NF) proteins as substrates, the kinase with a higher activity for the dephosphorylated NF-H than the phosphorylated form of NF-H was searched for in the porcine brain extract. Most NF-H kinase activity in the brain extract pelleted with microtubules. The NF-H kinase purified from a high salt extract of the microtubule pellets was composed of cdk5 and a 26 kDa protein, a fragment of the 35 kDa regulatory subunit of cdk5. In contrast to the association of the active kinase with microtubules, each of uncomplexed cdk5 and the 35 kDa regulatory subunit was differently distributed in the supernatant fraction and the pellet, respectively, by ultracentrifugation of the brain extract. Dephosphorylated forms of NF-H and NF-M became reactive to antibodies recognizing in vivo phosphorylation sites (SMI31, 34, and 36, JJ31 and 51) by phosphorylation with cdk5/p26. cdk5/p26 showed similar enzymatic properties to p34cdc2/cyclin B kinase; the substrate specificity and inhibition by a p34cdc2 kinase specific inhibitor, butyrolactone I. However, p34cdc2/cyclin B kinase was distinguished from cdk5/p26 by its binding to p13suc1 protein and by its reactivity to anti-p34cdc2 antibodies. In spite of similar enzymatic properties of cdk5/p26 and p34cdc2/cyclin B kinase, cdk5/p26 did not display M-phase promoting activity when assayed with a cell-free system of Xenopus egg extract.
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PMID:Porcine brain neurofilament-H tail domain kinase: its identification as cdk5/p26 complex and comparison with cdc2/cyclin B kinase. 755 15

We have identified and purified from bovine brain a novel protein kinase which catalyzes in vitro phosphorylation of neurofilament proteins NF-H and NF-M and tau proteins at sites implicating the enzyme in the regulation of neurocytoskeleton dynamics and in Alzheimer pathology. The protein kinase displays a phosphorylation site specificity similar or identical to the cell cycle regulatory kinase, cdc2 kinase. The purified kinase is a heterodimer of a cdc2-like catalytic subunit, called cdk5, and a 25 kDa regulatory subunit. The regulatory subunit is essential for kinase activity, and it is derived from a 35 kDa protein, p35 by proteolysis. Northern blot analysis of tissue distribution indicates that cdk5 is widely distributed but especially rich in brain, whereas p35 expression is only found in brain. The protein kinase is therefore termed neuronal cdc2-like kinase. The neuron-specificity of the enzyme appears to be conferred by the regulatory subunit. During cell division, cdc2 kinase is regulated by complex phosphorylation mechanisms involving a network of specific protein kinases. Some of these kinases or their homologs have been found in mammalian brains and they may be involved in the regulation of neuronal cdc2-like kinase.
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PMID:Structure, function, and regulation of neuronal Cdc2-like protein kinase. 756 36

Neuronal cdc2-like kinase, nclk, is a heterodimer of cyclin dependent protein kinase 5, cdk5, and a 25 kDa subunit derived from a novel, neuron-specific, 35 kDa protein: p35. The characterization and regulation of nclk will be summarized in this minireview. The activity of nclk appears to be governed by highly complex regulatory mechanisms including protein-protein interaction, protein phosphorylation and isoforms. The histone H1 kinase activity of nclk is absolutely dependent of the interaction between the 25 kDa subunit and the catalytic subunit, cdk5. In addition, nclk interacts with other cellular proteins to form macromolecular complexes. The kinase activity of nclk is inhibited in vitro by the phosphorylation reactions of a weel-like protein tyrosine kinase and a protein serine/threonine kinase from bovine thymus. Northern blot analysis has revealed the existence of two populations of p35 mRNA of 2 and 4 kb. A novel cDNA encoding a p35 homologous protein has been obtained from a human hippocampus library.
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PMID:Regulatory properties of neuronal cdc2-like kinase. 856 47

Meiotic maturation of fish oocytes is induced by the action of maturation-inducing hormone (MIH). 17 alpha,20 beta-Dihydroxy-4-pregnen-3-one (17 alpha,20 beta-DP) was identified as the MIH of several fish species, including salmonid fishes. The interaction of two ovarian follicle cell layers, the thecal and granulosa cell layers, is required for the synthesis of 17 alpha,20 beta-DP; the thecal layer produces 17 alpha-hydroxyprogesterone that is converted to 17 alpha,20 beta-DP in granulosa cells by the action of 20 beta-hydroxysteroid dehydrogenase (20 beta-HSD). The preovulatory surge of LH-like gonadotropin (GTH II) is responsible for rapid expression of 20 beta-HSD mRNA transcripts in granulosa cells. 17 alpha,20 beta-DP acts via a receptor on the plasma membrane of oocytes. A specific 17 alpha,20 beta-DP receptor has been identified and characterized from defolliculated oocytes of several fish species. The concentrations of 17 alpha,20 beta-DP membrane receptor increase immediately prior to oocyte maturation. The pertussis toxin-sensitive inhibitory G protein is involved in the signal transduction pathway of 17 alpha,20 beta-DP. The early steps following 17 alpha,20 beta-DP action involve the formation of the major mediator of this steroid, maturation-promoting factor, which consists of cdc2 kinase (34 kDa) and cyclin B (46-48 kDa). Immature oocytes contain only monomeric 35 kDa cdc2 and do not stockpile cyclin B, although immature oocytes contain mRNA for cyclin B. 17 alpha,20 beta-DP induces oocytes to synthesize cyclin B, which in turn activates preexisting 35 kDa cdc2 through its threonine 161 phosphorylation by a threonine kinase (M015), producing the 34-kDa active cdc2. 17 alpha,20 beta-DP-induced oocyte maturation is blocked by cordycepin, a polyadenylation inhibitor. Furthermore, cyclin B mRNA was polyadenylated during 17 alpha,20 beta-DP-induced oocyte maturation. These findings suggest that 17 alpha,20 beta-DP initiates translation of cyclin B mRNA through cytoplasmic 3' poly(A) elongation.
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PMID:17 alpha,20 beta-dihydroxy-4-pregnen-3-one, a maturation-inducing hormone in fish oocytes: mechanisms of synthesis and action. 902 36

We studied the subcellular distribution of cdk2 in synchronized, PDGF-stimulated human fibroblasts (FH109). After contact inhibition and serum depletion, more than 95% of FH109 cells were arrested in G0/G1-phase. PDGF-AB led to a 16-fold increase in proliferation compared with untreated cells. Cell cycle progression was studied by flow cytometric analysis, [3H]thymidine incorporation, and phosphorylation of the retinoblastoma gene product, pRB. Using Western blot analysis after subcellular fractionation, we revealed that after PDGF stimulation the phosphorylated (Thr 160), i.e., activated, form of cdk2 (33 kDa) first appeared in the nucleus at late G1-phase and persisted throughout until to the end of S-phase. Since cdk2 was not synthesized de novo, and the amount of inactive cdk2 (35 kDa) remained constant in the nucleus, we suggested a translocation from the cytosol to the nucleus in late G1. Using immunofluorescence techniques, we detected a diffuse staining in quiescent cells. Starting at late G1-phase, cdk2 immunoreactivity was concentrated to the nucleus while immunoreactivity in the cytosol disappeared. We therefore draw the conclusion that cdk2 is translocated from the cytosol into the nucleus in late G1-phase. Since protein levels and activity of cdk7, which is the catalytic subunit of cdk-activating kinase (CAK) phosphorylating cdk2, remained constant throughout the cell cycle, CAK activity might therefore be regulated by the availability of its substrate cdk2.
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PMID:Translocation of cdk2 to the nucleus during G1-phase in PDGF-stimulated human fibroblasts. 914 23

Neuronal Cdc2-like kinase, Nclk, is a heterodimer of a Cdk5 catalytic subunit and a 25 kDa regulatory subunit derived proteolytically from a neuron- and central nervous system-specific 35 kDa protein. The regulatory subunit is mandatory for kinase activity, hence it is designated the neuronal Cdk5 activator, p25/p35nck5a. Nclk has been suggested to play a regulatory role in neuro-cytoskeleton dynamics and in neuronal differentiation. In addition to the activation by Nck5a, Cdk5 is regulated by other mechanisms including additional activator proteins and inhibition by phosphorylation of specific amino acid residues. While Nclk shares common catalytic and regulatory properties with other members of the cdc2-like kinase family, it also displays unique characteristics that may be important for its neuronal functions.
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PMID:Neuronal Cdc2-like kinases: neuron-specific forms of Cdk5. 937 76

While cyclin-dependent kinase 5 (Cdk5) is widely distributed in mammalian tissues and in cultured cell lines, Cdk5-associated kinase activity has been demonstrated only in mammalian brains. An active form of Cdk5, called neuronal cdc2-like kinase (Nclk) has been purified from mammalian brain and shown to be a heterodimer of Cdk5 and a 25 kDa protein, which is derived proteolytically from a 35 kDa brain and neuron-specific protein. The protein is essential for the kinase activity of Cdk5 and is therefore designated neuronal Cdk5 activator, p25/35Nck5a. Nclk appears to have important neuronal functions. The changes in Cdk5 and Nck5a expression appear to correlate with the terminal differentiation of neurons of the mouse embryonic brain. Transfection of cultured cortical neurons with dominant negative cdk5 mutants or Nck5a antisense DNA may reduce neurite growth, suggesting that Nclk plays an active role in neuron differentiation. A number of cytoskeletal proteins including neurofilament proteins, the neuron-specific microtubule associated protein tau, and the actin binding protein caldesmon are in vitro substrates of Nclk. Although Nck5a has cyclin-like activity, it shows minimal amino acid sequence identity to members of cyclin family proteins. The mechanism of activation of Cdk5 by Nck5a differs from that of cyclin activation of Cdks in that full Cdk5 kinase activity can be achieved in the absence of phosphorylation of Cdk5. An isoform of Nck5a, a 39 kDa protein has been cloned and shown to share extensive amino acid identity and the mechanism of Cdk5 activation with Nck5a. These proteins may represent a subfamily of Cdk activators distinct from cyclins.
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PMID:Cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activators. 955 97

Two cdc2-related protein kinases (crk), tzcrk3 and tzcrk1, from the protozoan parasite Trypanosoma cruzi were cloned. tzcrk3 encodes a 35 kDa protein sharing 51.5% amino acid identity with human cdc2 and 82% identity with Trypanosoma brucei CRK3. tzcrk1 encodes a 33 kDa protein sharing 52.7% identity with human cdc2 and a high degree of identity (> 78%) with T. brucei CRK1, Leishmania mexicana CRK1 and Trypanosoma congolense CRK1. A recombinant TzCRK1 protein was able to phosphorylate histone HI and retinoblastoma protein. Western blotting using a polyclonal antibody raised against the recombinant TzCRK1 protein showed that the kinase is present in all life cycle stages of the parasite. A PSTAIRE antiserum detected proteins of 32, 33 and 35 kDa, with differential expression in the life cycle of the parasite. Transfection of COS-7 cells with tzcrk1 demonstrated for the first time that a CRK protein can bind mammalian cyclins; TzCRK1 co-immunoprecipitated with cyclins E, D3 and A suggesting a role for this kinase in cell cycle control. These results indicate that T. cruzi might have cyclin homologues that control the activity of the CRK proteins and that a complex mechanism would exist in order to regulate the kinases involved in the cell cycle and the differentiation processes of the parasite.
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PMID:Cloning of a cdc2-related protein kinase from Trypanosoma cruzi that interacts with mammalian cyclins. 958 May 32

There is strong evidence that estrogens are involved in the etiology, promotion and progression of a variety of cancers, including the cancers of the breast and endometrium. The Syrian hamster estrogen-induced, estrogen-dependent renal neoplasm is a well-established animal model used to elucidate the cellular and molecular mechanisms involved in solely estrogen-induced carcinogenic processes. G(1) cell cycle progression was studied in estrogen-induced early renal tumor foci and in large kidney tumors of castrated male hamsters. Levels of cyclin D1, cyclin E and retinoblastoma (pRb) proteins were higher in these renal neoplasias than in adjacent uninvolved renal tissue and kidneys from untreated, age-matched animals. Of particular interest is the presence of a predominant 35 kDa cyclin E protein variant form in primary renal tumors. In addition, amounts of the phosphorylated forms of cyclin-dependent kinases (cdk) 2 and 4 were decreased, and both RNA and protein levels of p27(kip1) (p27), a cyclin-dependent kinase inhibitor, were markedly higher in early and frank renal tumors than in adjacent uninvolved renal tissue and kidneys of untreated, age-matched animals. These changes in cell cycle components coincided with a rise in renal tumor cell proliferation. Binding of the elevated p27 protein to cyclin E, cdk2 and cdk4, however, was not impaired, suggesting that this cell cycle suppressor protein is functional. In addition, cyclin D1-, cdk2-, cdk4- and cyclin E-associated kinase activities were also lower in these estrogen-induced renal neoplasms than in untreated, age-matched kidneys. Interestingly, when compared with untreated kidney tissue, early and frank renal neoplasms had less of the 62 kDa native form of E2F1 and contained a 57 kDa variant form. Thus we have characterized an unusual deregulation of the cell cycle during estrogen-induced renal tumorigenesis in Syrian hamsters which still allows for estrogen-driven kidney tumor cell proliferation and may contribute to the early genomic instability found.
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PMID:Unusual deregulation of cell cycle components in early and frank estrogen-induced renal neoplasias in the Syrian hamster. 1113 5

The antitumor activity of the crude water extract from Gac fruit (Momordica cochinchinensis) was investigated in vivo and in vitro. A water extract prepared from 0.75 and 0.25 mg dry weight of Gac fruit per gram body weight was given daily to Balb/c mice (n=15/group). The water extract inhibited the growth of the colon 26-20 adenocarcinoma cell line, transplanted in Balb/c mice, reducing wet tumor weight by 23.6%. Histological and immunohistochemical results indicated that Gac water extract reduced the density of blood vessels around the carcinoma. The water extract also produced a marked suppression of cell proliferation in colon 26-20 and HepG2 cells. Cell cycle analysis demonstrated a significant accumulation of cells in the S phase by water extract. Immunoblotting showed that cyclin A, Cdk2, p27waf1/Kip1 were down-regulated, whereas the protein level of p21waf1/Cip1 was not decreased. Treatment of colon 26-20 cells with Gac extract induced necrosis rather than apoptosis. The antitumor component was confirmed as a protein with molecular weight of 35 kDa, retained in the water-soluble high molecular weight fraction. Thus, the bioactive antitumor compound in Gac extract is a protein, which is distinct from lycopene, another compound in Gac fruit with potential antitumor activity.
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PMID:Inhibition of tumor growth and angiogenesis by water extract of Gac fruit (Momordica cochinchinensis Spreng). 1575 81


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