Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Skp2 and its cofactor Cks1 are the substrate-targeting subunits of the SCF(Skp2-Cks1) (Skp1/Cul1/F-box protein) ubiquitin ligase complex that regulates entry into S phase by inducing the degradation of the cyclin-dependent kinase inhibitors p21 and p27 (ref. 1). Skp2 is an oncoprotein that often shows increased expression in human cancers; however, the mechanism that regulates its cellular abundance is not well understood. Here we show that both Skp2 and Cks1 proteins are unstable in G1 and that their degradation is mediated by the ubiquitin ligase APC/C(Cdh1) (anaphase-promoting complex/cyclosome and its activator Cdh1). Silencing of Cdh1 by RNA interference in G1 cells stabilizes Skp2 and Cks1, with a consequent increase in p21 and p27 proteolysis. Depletion of Cdh1 also increases the percentage of cells in S phase, whereas concomitant downregulation of Skp2 reverses this effect, showing that Skp2 is an essential target of APC/C(Cdh1). Expression of a stable Skp2 mutant that cannot bind APC/C(Cdh1) induces premature entry into S phase. Thus, the induction of Skp2 and Cks1 degradation in G1 represents a principal mechanism by which APC/C(Cdh1) prevents the unscheduled degradation of SCF(Skp2-Cks1) substrates and maintains the G1 state.
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PMID:Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. 1501 2

Addition of glucose to starved yeast cells elicits a dramatic restructuring of the transcriptional and metabolic state of the cell. While many components of the signaling network responsible for this response have been identified, a comprehensive view of this network is lacking. We have used global analysis of gene expression to assess the roles of the small GTP-binding proteins, Ras2 and Gpa2, in mediating the transcriptional response to glucose. We find that 90% of the transcriptional changes in the cell attendant on glucose addition are recapitulated by activation of Ras2 or Gpa2. In addition, we find that protein kinase A (PKA) mediates all of the Ras2 and Gpa2 transcriptional effects. However, we also find that most of the transcriptional effects of glucose addition to wild-type cells are retained in strains containing a PKA unresponsive to changes in cAMP levels. Thus, most glucose-responsive genes are regulated redundantly by a Ras/PKA-dependent pathway and by one or more PKA-independent pathways. Computational analysis extracted RRPE/PAC as the major response element for Ras and glucose regulation and revealed additional response elements mediating glucose and Ras regulation. These studies provide a paradigm for extracting the topology of signal transduction pathways from expression data.
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PMID:Ras and Gpa2 mediate one branch of a redundant glucose signaling pathway in yeast. 1513 98

Laryngeal carcinoma (LC) is the most commonly diagnosed malignancy and recently the incidence of this disease has increased. By means of the mRNA differential display method we identified a cDNA, Laryngeal carcinoma related gene 1 (LCRG1) which has significantly reduced expression in 40% (12/30) of primary LCs and in 6 of 10 various cancer cell lines. Northern Blot analysis showed that LCRG1 was expressed more abundantly in human heart, pancreas, skeletal muscle, and in murine testis, liver, brain and heart than in other tissues. The cDNA sequence of this gene is identical to part of the sequence of PAC HCIT75G16 clone (GenBank accession No. AC003042) from the chromosome band 17q12-21.1 which is one of the most common loss of heterozygosity (LOH) regions involved in LC, prostate cancer, etc. This gene is composed of six exons and spans about 60 kb of genomic DNA with a 3.4 kb mature transcript. The alignment of this gene with STS markers localized the gene to the previously identified tumor-suppressor locus D17S800-D17S930. The putative protein encoded by this gene is 288 amino acid with one potential site for phosphorylation by casein kinase II and no significant homology to any known proteins in the public databases. The primary tumor suppressive functions (proliferation rate,soft agar growth and tumor formation) were observed in a LC cell line (Hep-2) by lipofectin transfection. Together these data strongly suggest a potential role of LCRG1 contributing to the development of LC.
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PMID:Molecular cloning and characterization of LCRG1 a novel gene localized to the tumor suppressor locus D17S800-D17S930. 1514 23

Early mitotic inhibitor 1 (Emi1) inhibits the activity of the anaphase promoting complex/cyclosome (APC/C), which is a multisubunit ubiquitin ligase that targets mitotic regulators for degradation in exit from mitosis. Levels of Emi1 oscillate in the cell cycle: it accumulates in the S phase and is rapidly degraded in prometaphase. The degradation of Emi1 in early mitosis is necessary for the activation of APC/C in late mitosis. Previous studies have shown that Emi1 is targeted for degradation in mitosis by a Skp1-Cullin1 F-box protein (SCF) ubiquitin ligase complex that contains the F-box protein beta-TrCP. As with other substrates of SCF(beta-TrCP), the phosphorylation of Emi1 on a DSGxxS sequence is required for this process. However, the protein kinase(s) involved has not been identified. We find that Polo-like kinase 1 (Plk1), a protein kinase that accumulates in mitosis, markedly stimulates the ligation of Emi1 to ubiquitin by purified SCF(beta-TrCP). Cdk1-cyclin B, another major mitotic protein kinase, has no influence on this process by itself but stimulates the action of Plk1 at low, physiological concentrations. Plk1 phosphorylates serine residues in the DSGxxS sequence of Emi1, as suggested by the reduced phosphorylation of a derivative in which the two serines were mutated to nonphosphorylatable amino acids. Transfection with an small interfering RNA duplex directed against Plk1 caused the accumulation of Emi1 in mitotically arrested HeLa cells. It is suggested that phosphorylation of Emi1 by Plk1 is involved in its degradation in mitosis.
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PMID:Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. 1514 69

In order to prevent division of damaged chromosomes, cells activate a checkpoint to inhibit mitotic progression in order to repair the damaged DNA. Upon detection of DNA damage two downstream checkpoint kinases, Chk1 and Rad53, are activated by the sensor kinase, Mec1, to block the metaphase to anaphase transition and mitotic exit, respectively. Recent data from studies with budding yeast suggested that the DNA damage checkpoint also enlists the cAMP dependent protein kinase (PKA) pathway, which is an integral part of the nutrient sensing mechanism in budding yeast, to inhibit mitosis in response to DNA damage. Genetic and biochemical evidence suggested that the PKA pathway contributes to the inhibition of mitotic progression by mediating the phosphorylation of the APC specificity factor Cdc20. Phosphorylation of Cdc20 assists the activity of the checkpoint pathways in the inhibition of the degradation of mitotic inhibitors securin, Pds1, and the B type cyclin, Clb2, in order to block anaphase and mitotic exit. Cdc20 was phosphorylated following DNA damage in a PKA and Mec1 dependent manner, suggesting PKA activation is dependent on Mec1. Here we discuss possible mechanisms for how PKA activity could be regulated in response to DNA damage and we will also address the implication of these results in evaluating current cancer treatments.
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PMID:Stopped for repairs: a new role for nutrient sensing pathways? 1519 Feb 5

Here, we identified a new member of the Fizzy-related family of APC activators, Cru1, which is required for virulence in the corn smut fungus Ustilago maydis. We show that Cru1 promotes the degradation of B-type cyclins in U. maydis. Cells deficient in the Cru1 protein show defects in cell size, adaptation to nutritional conditions and cell separation. We propose that the phenotypes observed are a consequence of the inability of cru1 Delta cells to keep under control the levels of mitotic cyclins during G1. The levels of cru1 mRNA are controlled by nutritional conditions and cAMP levels, implicating the cAMP/protein kinase A pathway in the transmission of environmental conditions to the cell cycle. Cells deficient in Cru1 function are severely impaired in their ability to infect corn plants. This low rate of plant infection is caused by several defects. First, a low level of expression of the pheromone-encoding gene, mfa1, resulted in a low frequency of dikaryotic infective filament formation. Second, proliferation of fungal cells inside the plant is also affected, resulting in the inability to induce tumors in plants. Finally, the formation and germination of teliospores is also impaired. Our results support the hypothesis that virulence and cell cycle are connected in U. maydis. We propose that along the infection process, Cru1 is required to keep the appropriate G1 length necessary for the adaptation of fungal cells to host environment through the different stages of the plant infection.
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PMID:A member of the Fizzy-related family of APC activators is regulated by cAMP and is required at different stages of plant infection by Ustilago maydis. 1531 79

Cdh1 contributes to proper exit from mitosis and maintenance of G(1) phase in eukaryotic cells by activating a large ubiquitin ligase called the anaphase-promoting complex, or cyclosome (APC/C). At the end of G(1), APC/C(Cdh1) is inhibited by cyclin-dependent kinase (CDK) phosphorylation of Cdh1. The specific Cdh1 phosphorylation sites used to regulate APC/C(Cdh1) activity have not been directly identified. Here, we used a mass spectrometric approach to identify the in vivo phosphorylation sites on yeast Cdh1. Surprisingly, in addition to several expected CDK phosphorylation sites, we discovered numerous nonCDK phosphorylation sites. In total, at least 19 serine and threonine residues on Cdh1 are phosphorylated in vivo. Seventeen of these sites are located in the N-terminal half of Cdh1, outside the highly conserved WD40 repeats. The pattern of phosphorylation was the same when Cdh1 was purified from yeast cultures arrested in S, early M and late M. Mutation of CDK consensus sequences eliminated detectable phosphorylation at many of the nonCDK sites. In contrast, mutation of nonCDK sites had no significant effect on CDK phosphorylation. We conclude that phosphorylation of CDK sites promotes the subsequent recognition of Cdh1 by at least one additional kinase. The function of nonCDK phosphorylation may differ from CDK phosphorylation because mutation of nonCDK sites did not result in constitutive activation of APC and consequent cell cycle arrest. These results suggest that phosphoregulation of APC/C(Cdh1) activity is much more complex than previously thought.
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PMID:Multi-kinase phosphorylation of the APC/C activator Cdh1 revealed by mass spectrometry. 1546 59

Inappropriate activation of the Wnt/APC/beta-catenin signaling pathways plays a critical role at early stages in a variety of human cancers. However, their respective implication in tumor cell invasion is still hypothetical. Here, we show that two activators of the canonical Wnt/beta-catenin transcription pathway, namely Dvl-2, the Axin 501-560 fragment binding glycogen synthase kinase -3beta (GSK-3beta), and the negative Wnt regulator wt-Axin did not alter cell invasion into type I collagen. In addition, both Dvl-2 and Axin 501-560 exerted a permissive action on the proinvasive activity of HGF and intestinal trefoil factor. Upstream activation of Wnt signaling by the Wnt-2 and Wnt-3a ligands, stable overexpression of Wnt-2, as well as GSK-3beta inhibition by lithium, SB216763, and GSK-3beta dominant negative forms (K85R and R96E) conferred the invasive phenotype through several proinvasive pathways. Induction of the matrix metalloprotease MMP-7 (matrilysin) gene and protein by Wnt-2 was abolished by inactivation of the AP-1 binding site in the promoter. Accordingly, invasion induced by Wnt-2 was prevented by soluble FRP-3 and FRP-1, sequestration of Gbetagamma subunits, depletion of the GSK-3beta protein by RNA interference, the c-Jun dominant negative mutant TAM67 and was not reversed by wt-Axin. Thus, the proinvasive activity of Wnt-2 is mediated by a noncanonical Wnt pathway using GSK-3beta and the AP-1 oncogene. Our data provide a potential clue for our understanding of the action and crosstalk between Wnt activators and other proinvasive pathways, in relation with matrix substrates and proteases in human cancers.
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PMID:The proinvasive activity of Wnt-2 is mediated through a noncanonical Wnt pathway coupled to GSK-3beta and c-Jun/AP-1 signaling. 1550 71

Recently, experiments have shown that cyclin-dependent kinase (CDK) activity exhibits hysteresis in its response to total cyclin when cyclin is made nondegradable and controlled externally. This observation was taken to support mathematical modeling predictions regarding the underlying dynamics of the cell cycle. However, cell cycle dynamics can also be generated by other nonhysteretic mechanisms. To examine the robustness of the hysteretic response of CDK activity to total cyclin, we simulated various cell cycle signal transduction networks, and correlated the dynamics to the response function of CDK activity versus total cyclin. By randomly searching the parameter space, we assessed robustness by estimating the frequency of hysteretic versus nonhysteretic dynamical mechanisms. When the dynamical instabilities were caused by feedback loops in CDK phosphorylation and dephosphorylation or by feedback between cyclin and the CDK inhibitor, the response function of CDK activity versus total cyclin correlated well with the dynamical instabilities. However, when the dynamical instabilities originated from feedback between cyclin and APC-CDH1 or RB-E2F, the response function did not correlate with dynamical instabilities. Thus, although a hysteretic response is neither necessary nor sufficient, it is in general a much more robust mechanism for generating cell cycle dynamics than nonhysteretic mechanisms.
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PMID:Hysteresis and cell cycle transitions: how crucial is it? 1562 7

The Xenopus Polo-like kinase Plx1 plays multiple roles in mitosis. Accumulating evidence shows that Plx1 is the trigger kinase for the G2/M transition that phosphorylates and activates the phosphatase Cdc25C, which subsequently dephosphorylates Cdc2/cyclin B and initiates a positive feedback loop between Cdc25C and Cdc2/cyclin B. Recent findings indicate that Plx1 itself is also in a positive feedback loop. It phosphorylates and activates the protein kinase xPlkk1, which itself then phosphorylates and further activates Plx1. Plx1 functions on the centrosome to promote bipolar spindle formation. Plx1 associates with the anaphase-promoting complex/cyclosome (APC/C) and is required to activate the APC/C for degradation of mitotic regulators required for sister chromatid separation and exit from mitosis. Plx1 is also required for cytokinesis and is localized on the midbody of the contractile ring. All known functions of Plx1 require not only its kinase activity but also an intact polo box domain in the C-terminus.
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PMID:Xenopus Polo-like kinase Plx1: a multifunctional mitotic kinase. 1564 Aug 39


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