Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that overexpression of cell division autoantigen 1 (CDA1) in HeLa cells arrests cell growth and inhibits DNA synthesis at S-phase. Here we show that CDA1-induced arrest of cell growth is accompanied by increases in protein and mRNA levels of the cyclin-dependent kinase (Cdk) inhibitor protein, p21(Waf1/Cip1) (p21). Both p21 induction and cell growth arrest are reversed when CDA1 expression is inhibited. CDA1 also increases p53 protein, but not its mRNA, in a time- and dose-dependent manner. MDM2, a ubiquitin ligase regulating p53 degradation, is inactivated by CDA1, suggesting that p53 protein accumulation is due to decreased protein degradation. Knockdown of p53, using siRNA targeting two sites of p53 mRNA, abrogates transcriptional induction of p21 by CDA1. Deletion of the p53 responsive element in the distal region of p21 promoter attenuates promoter activity in response to CDA1. DNA damage caused by camptothecin treatment increases mRNA and protein levels of CDA1, accompanied by induction of p53. The DNA damage-induced p53 induction is markedly attenuated by CDA1 knockdown. CDA1 induces phosphorylation of ERK1/2(p44/42), an activity blocked by PD98059 and U0126, inhibitors of the upstream kinase MEK1/2. The MEK inhibitors also block induction of p21 mRNA and abrogate p21 promoter activity stimulated by CDA1. Cell cycle kinases, Cdk1, -2, -4, and -6 are inhibited by CDA1 overexpression. We conclude that CDA1 induces p53- and MEK/ERK1/2 MAPK-dependent expression of p21 by acting through the p53 responsive element in the p21 promoter and that this contributes to its antiproliferative activity.
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PMID:Antiproliferative autoantigen CDA1 transcriptionally up-regulates p21(Waf1/Cip1) by activating p53 and MEK/ERK1/2 MAPK pathways. 1731 70

Progression through meiosis in yeast is governed by the cyclin-dependent kinase Cdk1, in concert with a related kinase called Ime2. It remains unclear how these kinases collaborate to meet the unique demands of meiotic progression. We demonstrate that Ime2 and Cdk1 phosphorylate an overlapping substrate set and that the two kinases overlap functionally as inhibitors of the ubiquitin ligase APC(Cdh1) and replication origin licensing. Surprisingly, Ime2 phosphorylates Cdk1 substrates at distinct phosphorylation sites that are highly resistant to dephosphorylation by the phosphatase Cdc14. We propose that Ime2-dependent phosphorylation of a subset of cell-cycle proteins limits the effects of Cdc14 in meiosis.
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PMID:Evolution of Ime2 phosphorylation sites on Cdk1 substrates provides a mechanism to limit the effects of the phosphatase Cdc14 in meiosis. 1734 56

14-3-3 proteins are crucial in a wide variety of cellular responses including cell cycle progression, DNA damage checkpoints and apoptosis. One particular 14-3-3 isoform, sigma, is a p53-responsive gene, the function of which is frequently lost in human tumours, including breast and prostate cancers as a result of either hypermethylation of the 14-3-3sigma promoter or induction of an oestrogen-responsive ubiquitin ligase that specifically targets 14-3-3sigma for proteasomal degradation. Loss of 14-3-3sigma protein occurs not only within the tumours themselves but also in the surrounding pre-dysplastic tissue (so-called field cancerization), indicating that 14-3-3sigma might have an important tumour suppressor function that becomes lost early in the process of tumour evolution. The molecular basis for the tumour suppressor function of 14-3-3sigma is unknown. Here we report a previously unknown function for 14-3-3sigma as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B in a stoichiometric manner. Cells lacking 14-3-3sigma, in marked contrast to normal cells, cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells. The aberrant mitotic phenotype of 14-3-3sigma-depleted cells can be rescued by forced expression of p58 PITSLRE or by extinguishing cap-dependent translation and increasing cap-independent translation during mitosis by using rapamycin. Our findings show how aberrant mitotic translation in the absence of 14-3-3sigma impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3sigma-deficient cells may progress on the path to aneuploidy and tumorigenesis.
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PMID:14-3-3sigma controls mitotic translation to facilitate cytokinesis. 1736 Nov 71

Despite improvement in surgical techniques, prognosis of gallbladder carcinoma remains poor. It is desirable to identify prognostic biomarkers to aid in the development of targeted therapeutic strategies. Two SCF(Skp2) ubiquitin ligase-related proteins, Skp2 and cyclin-dependent kinase subunit 1 (Cks1), are involved in post-transcriptional degradation of p27(Kip1) tumor suppressor, which inhibits both cdk2/cyclin E and cdk2/cyclin A complexes and thus prevents transition to the S phase. However, the prognostic utility of p27(Kip1)-interacting cell cycle regulators has not been systematically assessed in gallbladder carcinoma. Immunohistochemistry was performed for p27(Kip1), Skp2, Cks1, cyclin E, cyclin A, and Ki-67 in tissue microarrays of 62 gallbladder carcinomas with follow-up. The data were correlated with clinicopathological features and overall survival (OS). The cumulative OS rate for all 62 cases was 42.9% at 3 years. Aberrant labeling indices (LIs) of p27(Kip1) (<20%), cyclin E (>or=5%), cyclin A (>or=5%), Cks1 (>or=40%), and Skp2 (>or=10%) were identified in 29, 58, 66, 21, and 57% of gallbladder carcinomas, respectively. By log-rank tests, downregulation of p27(Kip1) (P=0.0319) and high LIs of Skp2 (P=0.0006), Cks1 (P=0.0460), cyclin E (P=0.0070), and Ki-67 (P=0.0037) were predictive of inferior OS. Furthermore, the combined expression status of Skp2 and Ki-67 robustly defined three prognostically different groups (P=0.0001). In multivariate comparison, Skp2 overexpression represented the strongest independent adverse prognosticator (P=0.004, risk ratio (RR): 5.538), followed by Ki-67 LI >or=50% (P=0.016, RR: 3.254) and American Joint Committee on Cancer stages II-IV (P=0.013, RR: 3.163). In conclusion, aberrations of p27(Kip1)-interacting cell cycle regulators are common in gallbladder carcinomas. Skp2 overexpression is highly representative of biological aggressiveness and independently associated with poor OS, suggesting that it is a promising novel target for therapeutic intervention in aggressive cases. The combined assessment of Skp2 and Ki-67 LIs effectively risk-stratifies gallbladder carcinomas with different prognosis, which is worth being prospectively validated in future study.
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PMID:Skp2 is an independent prognosticator of gallbladder carcinoma among p27(Kip1)-interacting cell cycle regulators: an immunohistochemical study of 62 cases by tissue microarray. 1738 52

Genome stability requires that genomic DNA is replicated only once per cell cycle. The replication-licensing system ensures that the formation of prereplicative complexes is temporally separated from the initiation of DNA replication [1-4]. The replication-licensing factors Cdc6 and Cdt1 are required for the assembly of prereplicative complexes during G1 phase. During S phase, metazoan Cdt1 is targeted for degradation by the CUL4 ubiquitin ligase [5-8], and vertebrate Cdc6 is translocated from the nucleus to the cytoplasm [9, 10]. However, because residual vertebrate Cdc6 remains in the nucleus throughout S phase [10-13], it has been unclear whether Cdc6 translocation to the cytoplasm prevents rereplication [1, 2, 14]. The inactivation of C. elegans CUL-4 is associated with dramatic levels of DNA rereplication [5]. Here, we show that C. elegans CDC-6 is exported from the nucleus during S phase in response to the phosphorylation of multiple CDK sites. CUL-4 promotes the phosphorylation and subsequent translocation of CDC-6 via negative regulation of the CDK-inhibitor CKI-1. Rereplication can be induced by coexpression of nonexportable CDC-6 with nondegradable CDT-1, indicating that redundant regulation of CDC-6 and CDT-1 prevents rereplication. This demonstrates that CDC-6 translocation is critical for preventing rereplication and that CUL-4 independently controls both replication-licensing factors.
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PMID:C. elegans CUL-4 prevents rereplication by promoting the nuclear export of CDC-6 via a CKI-1-dependent pathway. 1771 48

Regulation of biological processes often involves phosphorylation of intrinsically disordered protein regions, thereby modulating protein interactions. Initiation of DNA replication in yeast requires elimination of the cyclin-dependent kinase inhibitor Sic1 via the SCF(Cdc4) ubiquitin ligase. Intriguingly, the substrate adapter subunit Cdc4 binds to Sic1 only after phosphorylation of a minimum of any six of the nine cyclin-dependent kinase sites on Sic1. To investigate the physical basis of this ultrasensitive interaction, we consider a mean-field statistical mechanical model for the electrostatic interactions between a single receptor site and a conformationally disordered polyvalent ligand. The formulation treats phosphorylation sites as negative contributions to the total charge of the ligand and addresses its interplay with the strength of the favorable ligand-receptor contact. Our model predicts a threshold number of phosphorylation sites for receptor-ligand binding, suggesting that ultrasensitivity in the Sic1-Cdc4 system may be driven at least in part by cumulative electrostatic interactions. This hypothesis is supported by experimental affinities of Cdc4 for Sic1 fragments with different total charges. Thus, polyelectrostatic interactions may provide a simple yet powerful framework for understanding the modulation of protein interactions by multiple phosphorylation sites in disordered protein regions.
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PMID:Polyelectrostatic interactions of disordered ligands suggest a physical basis for ultrasensitivity. 1752 59

Meiotic development in yeast requires the coordinated induction of transient waves of gene transcription. The present study investigates the regulation of Ume6p, a mitotic repressor of the "early" class of meiosis-specific genes. Western blot analysis revealed that Ume6p is destroyed early in meiosis by Cdc20p, an activator of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase. This control appears direct as Cdc20p and Ume6p associate in vivo and APC/C(Cdc20) ubiquitylates Ume6p in vitro. Inactivating Cdc20p, or stabilizing Ume6p through mutation, prevented meiotic gene transcription and meiotic progression. During mitotic cell division, Ume6p is protected from destruction by protein kinase A phosphorylation of Cdc20p. Complete elimination of Ume6p in meiotic cells requires association with the meiotic inducer Ime1p. These results indicate that Ume6p degradation is required for normal meiotic gene induction and meiotic progression. These findings demonstrate a direct connection between the transcription machinery and ubiquitin-mediated proteolysis that is developmentally regulated.
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PMID:Meiosis-specific destruction of the Ume6p repressor by the Cdc20-directed APC/C. 1788 68

Hedgehog (Hh) proteins signal by inhibiting the proteolytic processing of Ci/Gli family transcription factors and by increasing Ci/Gli-specific activity. When Hh is absent, phosphorylation of Ci/Gli triggers binding to SCF ubiquitin ligase complexes and consequent proteolysis. Here we show that multiple successively phosphorylated CK1 sites on Ci create an atypical extended binding site for the SCF substrate recognition component Slimb. GSK3 enhances binding primarily through a nearby region of Ci, which might contact an SCF component other than Slimb. Studies of Ci variants with altered CK1 and GSK3 sites suggest that the large number of phosphorylation sites that direct SCF(Slimb) binding confers a sensitive and graded proteolytic response to Hh, which collaborates with changes in Ci-specific activity to elicit a morphogenetic response. We also show that when Ci proteolysis is compromised, its specific activity is limited principally by Su(fu), and not by Cos2 cytoplasmic tethering or PKA phosphorylation.
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PMID:Regulation of Ci-SCFSlimb binding, Ci proteolysis, and hedgehog pathway activity by Ci phosphorylation. 1792 25

The cyclin-dependent kinase (CDK) inhibitor p16(INK4a) and the MDM2 ubiquitin ligase inhibitor p19(ARF) are critical to the regulation of cell cycle progression. Their loss by deletion, mutation or epigenetic silencing is a common molecular alteration in many human cancers. To investigate the role of p16(INK4a)/p19(ARF) deficiency in CNS tumor pathogenesis, pregnant mice bearing p16(-/-)/p19(-/-), p16(+/-)/p19(+/-), and p16(+/+)/p19(+/+) embryos were exposed transplacentally on gestation day 14 to a single dose of the potent carcinogen, ethylnitrosourea (ENU). p16(+/-)/p19(+/-) male mice treated with ENU developed meningial proliferative lesions with a high incidence (5/10). The incidence was lower in other ENU-treated animals of both sexes and none occurred in saline-treated control animals. The lesions ranged from widespread meningeal proliferation and plaque-like thickening by neoplastic spindle cells consistent with meningiomatosis to a larger discrete mass consistent with a meningioma. Ultrastructural analysis revealed the presence of intercellular junctions between cells, supporting a meningothelial histogenesis. Spontaneous meningiomas occur rarely in wild-type mice but are a common neoplasm afflicting humans, accounting for between 13 and 26% of primary intracranial neoplasms. This ENU inducible meningeal lesion in p16(+/-)/p19(+/-) mice may provide additional insight into the pathogenesis of meningeal neoplasia and aid the development of therapeutics.
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PMID:N-ethyl-N-nitrosourea (ENU)-induced meningiomatosis and meningioma in p16(INK4a)/p19(ARF) tumor suppressor gene-deficient mice. 1794 59

Cells respond to DNA double-strand breaks by recruiting factors such as the DNA-damage mediator protein MDC1, the p53-binding protein 1 (53BP1), and the breast cancer susceptibility protein BRCA1 to sites of damaged DNA. Here, we reveal that the ubiquitin ligase RNF8 mediates ubiquitin conjugation and 53BP1 and BRCA1 focal accumulation at sites of DNA lesions. Moreover, we establish that MDC1 recruits RNF8 through phosphodependent interactions between the RNF8 forkhead-associated domain and motifs in MDC1 that are phosphorylated by the DNA-damage activated protein kinase ataxia telangiectasia mutated (ATM). We also show that depletion of the E2 enzyme UBC13 impairs 53BP1 recruitment to sites of damage, which suggests that it cooperates with RNF8. Finally, we reveal that RNF8 promotes the G2/M DNA damage checkpoint and resistance to ionizing radiation. These results demonstrate how the DNA-damage response is orchestrated by ATM-dependent phosphorylation of MDC1 and RNF8-mediated ubiquitination.
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PMID:Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. 1800 5


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