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)

A new structural type of kinase inhibitor, containing a benzocarbazole nucleus, has been identified. Members of the series are selective for inhibition of the cyclin dependent kinase family of enzymes. Although the cdks are highly homologous, representatives of the series showed intra-cdk selectivities, especially for cdk4. SAR studies elucidated the important features of the molecules for inhibition.
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PMID:Identification of selective inhibitors of cyclin dependent kinase 4. 1151 72

Protein kinase A regulatory subunit RIIalpha is tightly bound to centrosomal structures during interphase through interaction with the A-kinase anchoring protein AKAP450, but dissociates and redistributes from centrosomes at mitosis. The cyclin B-p34(cdc2) kinase (CDK1) has been shown to phosphorylate RIIalpha on T54 and this has been proposed to alter the subcellular localization of RIIalpha. We have made stable transfectants from an RIIalpha-deficient leukemia cell line (Reh) that expresses either wild-type or mutant RIIalpha (RIIalpha(T54E)). When expressed, RIIalpha detaches from centrosomes at mitosis and dissociates from its centrosomal location in purified nucleus-centrosome complexes by incubation with CDK1 in vitro. By contrast, centrosomal RIIalpha(T54E) is not redistributed at mitosis, remains mostly associated with centrosomes during all phases of the cell cycle and cannot be solubilized by CDK1 in vitro. Furthermore, RIIalpha is solubilized from particular cell fractions and changes affinity for AKAP450 in the presence of CDK1. D and V mutations of T54 also reduce affinity for the N-terminal RII-binding domain of AKAP450, whereas small neutral residues do not change affinity detected by surface plasmon resonance. In addition, only RIIalpha(T54E) interacts with AKAP450 in a RIPA-soluble extract from mitotic cells. Finally, microtubule repolymerization from mitotic centrosomes of the RIIalpha(T54E) transfectant is poorer and occurs at a lower frequency than that of RIIalpha transfectants. Our results suggest that T54 phosphorylation of RIIalpha by CDK1 might serve to regulate the centrosomal association of PKA during the cell cycle.
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PMID:CDK1-mediated phosphorylation of the RIIalpha regulatory subunit of PKA works as a molecular switch that promotes dissociation of RIIalpha from centrosomes at mitosis. 1159 13

The molecular interactions between PARP I, cdc2-kinase, PKC and histone H1 were determined with the aid of the common phosphate acceptor function of histone H1 to both kinases. PKC phosphorylates both histone H1 and PARP I and PARP I augments the acceptor function of histone H1. When both acceptors (PARP I and histone H1) are present an apparent distributive phosphorylation of both acceptors takes place. In contrast, cdc2-kinase only phosphorylates histone H1, and the activation of this reaction by PARP I does not involve PARP I-cdc2-kinase binding only PARP I-histone H1 association. Since the phosphorylation of histone H1 by PKC is a model reaction with no apparent physiologic consequences, the PARP I activated phosphorylation of histone H1 by cdc2-kinase, by contrast, reflects a physiologically meaningful regulation of the linker histone by a cyclin dependent kinase (cdc2-kinase). The increased phosphorylation of histone H1 by cdc2-kinase following PARP I-histone H1 binding results in the appearance of new phosphorylated histone H1 polypeptides as measured by proteolytic digestion and re-electrophoresis of cdc2-kinase phosphorylated polypeptides, indicating a probable conformational change in histone H1, following PARP I binding. The cell biologic significance of this reaction in PARP I ligand-induced enzyme induction is briefly analysed.
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PMID:Selective augmentation of histone H1 phosphorylation sites by interaction of poly(ADP-ribose) polymerase and cdc2-kinase: comparison with protein kinase C. 1171 87

The signal transduction pathway regulated by the retinoblastoma tumor suppressor protein, pRB, is abrogated in the majority of human cancers. Using a series of cell lines derived from oral squamous cell carcinomas (SCCs) that were not subjected to radiation or chemotherapy treatment, we detected specific hyperactivity of cyclin dependent kinase (cdk) 6 but not cdk4. Subcellular localization studies showed a predominant nuclear localization of cdk6, demonstrating that this kinase was biologically active. The molecular basis for this aberration are mutations in the MTS1 locus of chromosome 9p21. This locus encodes two partially overlapping genes, the cdk inhibitor p16(ink4a), and p14(ARF), an inhibitor of mdm2-mediated degradation of p53. Our analysis demonstrates that the mutations of the MTS1 locus in oral SCC specifically target expression of the p16(ink4a) gene but less frequently affect p14(ARF). These results suggest that hyperactivity of cdk6 represents a distinct mechanism for pRB inactivation in oral SCC.
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PMID:Aberrations in the MTS1 tumor suppressor locus in oral squamous cell carcinoma lines preferentially affect the INK4A gene and result in increased cdk6 activity. 1185 66

The development of malignant gliomas (astrocytomas) involves the accumulation of multiple genetic changes, including mutations in the p53 and retinoblastoma (Rb) cell cycle regulatory pathways. One Rb pathway alteration seen in high-grade astrocytomas is amplification of cyclin dependent kinase-4 (CDK4). To define the function of CDK4 amplification/overexpression in astrocytoma pathogenesis, we generated three transgenic mouse lines that overexpress human CDK4 (hCDK4) in astrocytes using the human glial fibrillary acidic protein (GFAP) promoter. GFAP-hCDK4 mice do not develop brain tumors, but exhibit a small increase in astrocyte number. Cultured astrocytes from these mice do not demonstrate a cell-autonomous growth advantage in vitro and lack properties of transformed cells. To determine whether cdk4 overexpression provides a cooperative growth advantage in vitro, CDK4-overexpressing C6 glioma cell lines were generated and found to exhibit increased cell growth. In addition, GFAP-hCDK4; p53+/- as well as p53+/-; Rb+/- mice exhibited increased numbers of astrocytes compared to GFAP-hCDK4, p53+/-, or Rb+/- mice in vivo. No cooperative effect was observed with GFAP-hCDK4; Rb+/- mice. These results support the hypothesis that cdk4 overexpression alone is not sufficient for astrocytoma formation, but can provide a cooperative growth advantage in concert with genetic alterations in the p53 pathway.
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PMID:Astrocyte-specific expression of CDK4 is not sufficient for tumor formation, but cooperates with p53 heterozygosity to provide a growth advantage for astrocytes in vivo. 1185 76

In this study, we examined the expression of cyclins, cyclin dependent kinase (CDKs) and CDK inhibitors by immunohistochemical analysis in 20 normal mucosa, 42 epithelial dysplasia (ED), and 117 oral squamous cell carcinoma. Neither Cyclin D1 nor CDK2 were detectable in normal tissue and ED. Their presence, however, was detectable in squamous cell carcinoma (SCCs) (Cyclin D1, 35.9%; CDK2, 66.7%). Cyclin E was detectable in 57.1% of severe ED and 62.8% of SCCs. For the CDK inhibitors, these proteins were detectable in all normal mucosa and most of the mild and moderate ED. For severe ED, expression of these proteins was not observed in some cases (p12(DOC-1), 14.3%; p16(INK4A), 28.6%; p27(KIP1), 7.1%). For SCCs, the expression of p12(DOC-1) was lost in 71.8%, p16(INK4A) in 69.2% and p27(KIP1) in 35.9%. These results suggest that elevated expression of cyclin D1, cyclin E, CDK2 and loss of p12(DOC-1), p16(INK4A) and p27(KIP1) may contribute to the multistep nature of oral carcinogenesis.
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PMID:Expression of cell cycle control proteins in normal epithelium, premalignant and malignant lesions of oral cavity. 1197 45

Mutations in the Presenilin 1 gene are the cause of the majority of autosomal dominant familial forms of Alzheimer's disease. Presenilin 1 (PS1) is produced as a holoprotein but is then rapidly processed to amino- (N-PS1) and carboxy-terminal (C-PS1) fragments that are incorporated into stable high molecular mass complexes. The mechanisms that control PS1 cleavage and stability are not properly understood but sequences within C-PS1 have been shown to regulate both of these properties. Here we demonstrate that cyclin dependent kinase-5/p35 (cdk5/p35) phosphorylates PS1 on threonine(354) within C-PS1 both in vitro and in vivo. Threonine(354) phosphorylation functions to selectively stabilize C-PS1. Our results demonstrate that cdk5/p35 is a regulator of PS1 metabolism.
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PMID:Cyclin-dependent kinase-5/p35 phosphorylates Presenilin 1 to regulate carboxy-terminal fragment stability. 1205 36

Multi-cellular spheroids (MCS) generated from tumor cells serve as excellent in vitro models for understanding the mechanisms of tumor progression and micro-metastasis. We have compared the expression of molecular markers with reference to their growth as conventional adherent monolayers (2-D) and anchorage independent cultures (3-D) using two mouse melanoma cell lines, B16F10 and Clone M3. The two cell lines differed in their ability to form spheroids with respect to their aggregation potential, with B16F10 forming large clusters compared to Clone M3. A panel of molecular markers comprising cell adhesion molecules, cyclin dependent kinase inhibitors and members of the cadherin-catenin complex were analyzed by flow cytometry in 2-D and 3-D cultures. There was a distinct difference in the patterns of expression of CD44(S) and variant isoforms v3, v10 in spheroids compared to cells grown as monolayers in both cell lines. Also, there was an increase in cells positive for CDK inhibitor p27 in 3-D cultures from the B16F10 cell line. The expression of alpha and gamma catenin was down regulated in spheroids. As these molecules are implicated in the regulation of cell proliferation, alterations in the expression of these molecules in 3-D cultures compared to their 2-D counterparts suggests the importance of spheroids as experimental model for tumorigenesis.
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PMID:Differential expression of CD44(S) and variant isoforms v3, v10 in three-dimensional cultures of mouse melanoma cell lines. 1219 73

Using a data set comprised of literature compounds and structure-activity data for cyclin dependent kinase 2, several pharmacophore hypotheses were generated using Catalyst and evaluated using several criteria. The two best were used in retrospective searches of 10 three-dimensional databases containing over 1,000,000 proprietary compounds. The results were then analyzed for the efficiency with which the hypotheses performed in the areas of compound prioritization, library prioritization, and library design. First as a test of their compound prioritization capabilities, the pharmacophore models were used to search combinatorial libraries that were known to contain CDK active compounds to see if the pharmacophore models could selectively choose the active compounds over the inactive compounds. Second as a test of their utility in library design again the pharmacophore models were used to search the active combinatorial libraries to see if the key synthons were over represented in the hits from the pharmacophore searches. Finally as a test of their ability to prioritize combinatorial libraries, several inactive libraries were searched in addition to the active libraries in order to see if the active libraries produced significantly more hits than the inactive libraries. For this study the pharmacophore models showed potential in all three areas. For compound prioritization, one of the models selected active compounds at a rate nearly 11 times that of random compound selection though in other cases models missed the active compounds entirely. For library design, most of the key fragments were over represented in the hits from at least one of the searches though again some key fragments were missed. Finally, for library prioritization, the two active libraries both produced a significant number of hits with both pharmacophore models, whereas none of the eight inactive libraries produced a significant number of hits for both models.
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PMID:Use of catalyst pharmacophore models for screening of large combinatorial libraries. 1237 10

We have investigated the cell growth inhibitory effects of crude catechin (catechin) containing approximately 53% of epigallocatechin-3-gallate (EGCG) on the human breast cancer cell line T47D, and the mechanism of its action, with emphasis on the cell cycle and mitogen-activated protein kinases (MAPK). A significant dose-dependent growth inhibition was observed after treatment with catechin. At 48 h after the addition of catechin, cells at the G2/M phase were increased by 8.3%, compared with the control. Analysis of the expression of cell cycle-related proteins after the addition of catechin showed that the cyclin-dependent kinase (cdk) 2 and the cdk4 proteins were decreased after administration, the expression of cyclin A protein was increased at 24 h after administration, however, the expression of the cyclin D1 and cyclin E proteins was unchanged. At 24 h after the administration of catechin, the phosphorylation of cell division cycle 2 (cdc2) was inhibited, and the expression of cyclin B1 protein was also decreased. Furthermore, the analysis of the MAPK expression showed that the phosphorylated JNK/SAPK protein began to increase at 3 h after catechin administration, and the expression persisted until 24 h after administration, then decreased. The phosphorylation of p38 protein was increased at 12 h, and began to decrease at 36 h after catechin administration. Based on these results, we speculate that, in the breast cancer cell line T47D, catechin phosphorylated JNK/SAPK and p38, and that the phosphorylated JNK/SAPK and p38 inhibited the phosphorylation of cdc2, and regulated the expression of cyclin A, cyclin B1, and cdk proteins, thereby causing G2 arrest. The results suggested that catechin (EGCG) may be an effective adjuvant therapy after breast cancer surgery.
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PMID:Analysis of cell growth inhibitory effects of catechin through MAPK in human breast cancer cell line T47D. 1242 81


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