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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated Wnt signaling pathways have been found in various human cancers, including those of the colon, liver, endometrium, ovary, prostate, and stomach. As a result, beta-catenin is accumulated and becomes transcriptionally active for proliferative genes and oncogenes. Wnt pathway mutations result in biochemical mechanisms yielding inefficient phosphorylation of beta-catenin by GSK3beta due to APC, beta-catenin and/or axin mutations. Therefore, the needs and the opportunity to develop new cancer therapies exist through reversing oncogenic APC/beta-catenin/Lef/Tcf signals. Exisulind and analogues are inhibitors of cyclic GMP phosphodiesterases (PDE) that have been shown to activate and induce protein kinase G. The data show PKG regulation of beta-catenin in wnt signaling, accounting, at least in part, for apoptosis induction in treated colon cancer cells carrying either APC or beta-catenin mutations. Exisulind and analogs reduce beta-catenin via a novel, GSK3beta independent processing mechanism. Activated PKG directly phosphorylate beta-catenin at its C-terminal domain and causes proteasome dependent degradation of the protein. Since this pathway is independent of APC and GSK3beta, exisulind and analogs provide a superior approach to circumvent the molecular defects of wnt signaling pathway and to treat cancers with such defects.
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PMID:beta-Catenin signaling: therapeutic strategies in oncology. 1264 83

Host resistance to the intracellular protozoan Leishmania major is highly dependent on IL-12 production by APCs. Genetically resistant C57BL/6 mice develop IL-12-mediated Th1 immune response dominated by IFN-gamma and exhibit only small cutaneous lesions that resolve spontaneously. In contrast, because of several genetic differences, BALB/c mice develop an IL-4-mediated Th2 immune response and a chronic mutilating disease. Myeloid differentiation marker 88 (MyD88) is an adaptator protein that links the IL-1/Toll-like receptor family to IL-1R-associated protein kinase. Toll-like receptors recognize pathogen associated molecular patterns and are crucially implicated in the induction of IL-12 secretion by APC. The role of MyD88 protein in the development of protective immune response against parasites is largely unknown. Following inoculation of L. major, MyD88(-/-) C57BL/6 mice presented large footpad lesions containing numerous infected cells and frequent mutilations. In response to soluble Leishmania Ag, cells from lesion-draining lymph node showed a typical Th2 profile, similar to infected BALB/c mice. IL-12p40 plasma level collapses in infected MyD88(-/-) mice compared with infected wild-type C57BL/6 mice. Importantly, administration of exogenous IL-12 rescues L. major-infected MyD88(-/-) mice, demonstrating that the susceptibility of these mice is a direct consequence of IL-12 deficiency. In conclusion, MyD88-dependent pathways appear essential for the development of the protective IL-12-mediated Th1 response against the Leishmania major parasite. In absence of MyD88 protein, infected mice develop a nonprotective Th2 response.
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PMID:Genetically resistant mice lacking MyD88-adapter protein display a high susceptibility to Leishmania major infection associated with a polarized Th2 response. 1268 57

Proteolysis triggered by the anaphase-promoting complex/cyclosome (APC/C) is essential for the progression through mitosis. APC/C is a highly conserved ubiquitin ligase whose activity is regulated during the cell cycle by various factors, including spindle checkpoint components and protein kinases. The cAMP-dependent protein kinase (PKA) was identified as negative regulator of APC/C in yeast and mammalian cells. In the yeast Saccharomyces cerevisiae, PKA activity is induced upon glucose addition or by activated Ras proteins. This study shows that glucose and the activated Ras2(Val19) protein synergistically inhibit APC/C function via the cAMP/PKA pathway in yeast. Remarkably, Ras2 proteins defective in the interaction with adenylate cyclase fail to influence APC/C, implying that its function is regulated exclusively by PKA, but not by alternative Ras pathways. Furthermore, it is shown that the three PKAs in yeast, Tpk1, Tpk2 and Tpk3, have redundant functions in regulating APC/C in response to glucose medium. Single or double deletions of TPK genes did not prevent inhibition of APC/C, suggesting that each of the Tpk proteins can take over this function. However, Tpk2 seems to inhibit APC/C function more efficiently than Tpk1 and Tpk3. Finally, evidence is provided that Cdc20 is involved in APC/C regulation by the cAMP/PKA pathway.
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PMID:Synergistic inhibition of APC/C by glucose and activated Ras proteins can be mediated by each of the Tpk1-3 proteins in Saccharomyces cerevisiae. 1272 82

Hormone regulation of anterior pituitary expression of the common glycoprotein hormone alpha-subunit (alphaGSU) is mediated by multiple response elements residing in the first -435 bp of the human promoter. In rat pituitary cells and mouse alphaT3-1 precursor gonadotrophs, the human alphaGSU promoter is strongly responsive to activators of the adenylyl cyclase/cAMP pathway, such as the hypothalamic releasing hormone, pituitary adenylate cyclase-activating polypeptide (PACAP) and forskolin (an adenylyl cyclase activator). However, the role of PACAP and cAMP in regulating alphaGSU transcription in the more differentiated LbetaT2 gonadotroph is unclear. Here, we investigate the regulation of the human alphaGSU promoter by PACAP and forskolin in LbetaT2 and alphaT3-1 gonadotrophs. PACAP failed to stimulate alphaGSU promoter activity or cAMP production in LbetaT2 cells, in marked contrast to alphaT3-1 cells. LbetaT2 gonadotrophs expressed extremely low levels of any PACAP type 1 receptors (PAC(1)-R) isoform by RT-PCR and lacked PAC(1)-R by radioligand binding. Forskolin stimulated the alphaGSU promoter in LbetaT2 cells, but by less than 30% of the response seen in alphaT3-1 gonadotrophs. This blunted cAMP transcriptional effect was not due to different levels of cAMP generation, or altered expression of the cAMP target proteins CREB, Akt, CBP or ICER. However, only LbetaT2 cells showed detectable expression of the protein kinase A type IIalpha regulatory subunit. Binding of activating transcription factor-2 and phosphorylated CREB to the consensus CRE was observed in both LbetaT2 and alphaT3-1 gonadotrophs, yet forskolin failed to stimulate either CRE- or CREB-mediated transcription in LbetaT2 cells. Collectively, these data demonstrate the lack of functional PACAP receptors in LbetaT2 gonadotrophs, and a pronounced attenuation in the responsiveness of this differentiated gonadotroph cell line to cAMP stimulus.
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PMID:Absence of pituitary adenylate cyclase-activating polypeptide-stimulated transcription of the human glycoprotein alpha-subunit gene in LbetaT2 gonadotrophs reveals disrupted cAMP-mediated gene transcription. 1451 95

The spindle checkpoint prevents anaphase onset until completion of mitotic spindle assembly by restraining activation of the ubiquitin ligase anaphase-promoting complex/cyclosome-Cdc20 (APC/CCdc20). We show that the spindle checkpoint requires mitotic cyclin-dependent kinase (cdk) activity. Inhibiting cdk activity overrides checkpoint-dependent arrest in Xenopus egg extracts and human cells. Following inhibition, the interaction between APC/C and Cdc20 transiently increases while the inhibitory checkpoint protein Mad2 dissociates from Cdc20. Cdk inhibition also overcomes Mad2-induced mitotic arrest. In addition, in vitro cdk1-phosphorylated Cdc20 interacts with Mad2 rather than APC/ C. Thus, cdk activity is required to restrain APC/CCdc20 activation until completion of spindle assembly.
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PMID:The spindle checkpoint requires cyclin-dependent kinase activity. 1456 75

Cdh1p, a substrate specificity factor for the cell cycle-regulated ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C), promotes exit from mitosis by directing the degradation of a number of proteins, including the mitotic cyclins. Here we present evidence that Cdh1p activity at the M/G(1) transition is important not only for mitotic exit but also for high-fidelity chromosome segregation in the subsequent cell cycle. CDH1 showed genetic interactions with MAD2 and PDS1, genes encoding components of the mitotic spindle assembly checkpoint that acts at metaphase to prevent premature chromosome segregation. Unlike cdh1delta and mad2delta single mutants, the mad2delta cdh1delta double mutant grew slowly and exhibited high rates of chromosome and plasmid loss. Simultaneous deletion of PDS1 and CDH1 caused extensive chromosome missegregation and cell death. Our data suggest that at least part of the chromosome loss can be attributed to kinetochore/spindle problems. Our data further suggest that Cdh1p and Sic1p, a Cdc28p/Clb inhibitor, have overlapping as well as nonoverlapping roles in ensuring proper chromosome segregation. The severe growth defects of both mad2delta cdh1delta and pds1delta cdh1dDelta strains were rescued by overexpressing Swe1p, a G(2)/M inhibitor of the cyclin-dependent kinase, Cdc28p/Clb. We propose that the failure to degrade cyclins at the end of mitosis leaves cdh1delta mutant strains with abnormal Cdc28p/Clb activity that interferes with proper chromosome segregation.
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PMID:The role of Cdh1p in maintaining genomic stability in budding yeast. 1457 64

Malignant mesothelioma is an aggressive disease of the pleura, and less commonly the peritoneum, with a very poor prognosis. The present study has examined the expression of cell adhesion molecules including cadherins, catenins, and APC in order to determine whether abnormal expression of components of the Wnt signalling pathway contribute to the variable phenotype of malignant mesothelioma. Sixty-three malignant mesotheliomas and nine cases of reactive mesothelial hyperplasia were analysed by immunohistochemistry for E-cadherin, N-cadherin, alpha-catenin, beta-catenin, and the C- and N-terminals of APC. In addition, DNA was extracted from formalin-fixed, paraffin wax blocks, and a 226 bp fragment of exon 3 of the beta-catenin gene was amplified, sequenced, and screened for activating mutations in the glycogen synthase kinase 3beta (GSK-3beta) phosphorylation targets. E-cadherin expression was detected in 48% of the epithelioid mesotheliomas but was observed in only 7% of sarcomatoid mesotheliomas. N-cadherin, alpha-catenin, beta-catenin, and the C- and N-terminals of APC did not show differential expression between the mesothelioma phenotypes. Abnormal nuclear localization of beta-catenin was demonstrated in 19% of mesotheliomas. Mutations of beta-catenin phosphorylation sites were not detected in any of the 62 mesotheliomas examined. Positive staining for the N-terminal of APC was seen in all of the cases of reactive mesothelial hyperplasia, as well as in all the mesotheliomas. Staining for the C-terminal of APC was negative in 23% mesotheliomas, despite being present in all the cases of reactive hyperplasia. The present study provides the first evidence that beta-catenin accumulates in the nucleus in malignant mesotheliomas. In addition, APC expression was altered in some mesotheliomas, suggesting that a truncated APC gene product may contribute to abnormal Wnt signalling and dysregulation of cell proliferation in malignant mesothelioma.
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PMID:Cadherins, catenins and APC in pleural malignant mesothelioma. 1459 46

1. The mechanisms and receptors involved in the vasoactive intestinal peptide (VIP)- and pituitary adenylate cyclase-activating polypeptide (PACAP)-induced relaxations of the pig intravesical ureter were investigated. 2. VIP, PACAP 38 and PACAP 27 concentration-dependently relaxed U46619-contracted ureteral strips with a similar potency. [Ala(11,22,28)]-VIP, a VPAC(1) agonist, showed inconsistent relaxations. 3. The neuronal voltage-gated Ca(2+) channel inhibitor, omega-conotoxin GVIA (omega-CgTX, 1 microm), reduced the VIP relaxations. Urothelium removal or blockade of capsaicin-sensitive primary afferents, nitric oxide (NO) synthase and guanylate cyclase with capsaicin (10 microm), N(G)-nitro-l-arginine (l-NOARG, 100 microm) and 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 microm), respectively, did not change the VIP relaxations. However, the PACAP 38 relaxations were reduced by omega-CgTX, capsaicin, l-NOARG and ODQ. 4. The VIP and VIP/PACAP receptor antagonists, [Lys(1), Pro(2,5), Arg(3,4), Tyr(6)]-VIP (1 microm) and PACAP (6-38) (0.4 microm), inhibited VIP and VIP and PACAP 38, respectively, relaxations. 5. The nonselective and large-conductance Ca(2)-activated K(+) channel blockers, tetraethylammonium (3 mm) and charybdotoxin (0.1 microm), respectively, and neuropeptide Y (0.1 microm) did not modify the VIP relaxations. The small-conductance Ca(2)-activated K(+) channel blocker apamin (1 microm) did not change the PACAP 27 relaxations. 6. The cAMP-dependent protein kinase A (PKA) blocker, 8-(4-chlorophenylthio)adenosine-3',5'-cyclic monophosphorothioate (Rp-8-CPT-cAMPS, 100 microm), reduced VIP relaxations. The phosphodiesterase 4 inhibitor rolipram and the adenylate cyclase activator forskolin relaxed ureteral preparations. The rolipram relaxations were reduced by Rp-8-CPT-cAMPS. Forskolin (30 nm) evoked a potentiation of VIP relaxations. 7. These results suggest that VIP and PACAP relax the pig ureter through smooth muscle receptors, probably of the VPAC(2) subtype, linked to a cAMP-PKA pathway. Neuronal VPAC receptors localized at motor nerves and PAC(1) receptors placed at sensory nerves and coupled to NO release, seem also to be involved in the VIP and PACAP 38 relaxations.
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PMID:Heterogeneity of neuronal and smooth muscle receptors involved in the VIP- and PACAP-induced relaxations of the pig intravesical ureter. 1466 37

In late mitosis and G1, a complex of the essential initiation proteins Mcm2-7 are assembled onto replication origins to 'license' them for initiation. At other times licensing is inhibited by cyclin-dependent kinases (CDKs) and geminin, thus ensuring that origins fire only once per cell cycle. Here we show that, paradoxically, CDKs are also required to inactivate geminin and activate the licensing system. On exit from metaphase in Xenopus laevis egg extracts, CDK-dependent activation of the anaphase-promoting complex (APC/C) results in the transient polyubiquitination of geminin. This ubiquitination triggers geminin inactivation without requiring ubiquitin-dependent proteolysis, and is essential for replication origins to become licensed. This reveals an unexpected role for CDKs and ubiquitination in activating chromosomal DNA replication.
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PMID:Non-proteolytic inactivation of geminin requires CDK-dependent ubiquitination. 1476 79

Two multiprotein E3 (ubiquitin-protein ligase) ubiquitin ligases, the SCF (Skp1-Cullin-1-F-box) and the APC/C (anaphase promoting complex/cyclosome), are vital in ensuring the temporal order of the cell cycle. Particularly, timely destruction of cyclins via these two E3s is essential for down-regulation of cyclin-dependent kinase. In general, G(1) and S phase cyclins are ubiquitylated by the SCF, whereas ubiquitylation of mitotic cyclins is catalyzed by the APC/C. Here we show that fission yeast S phase cyclin Cig2 is ubiquitylated and degraded via both the SCF and the APC/C. Cig2 instability during G(2) and M phase is dependent upon the SCF complex, whereas the APC/C is responsible for Cig2 destruction during anaphase and G(1), thereby ensuring a spike pattern of Cig2 levels, peaking only at S phase. Two F-box/WD proteins Pop1 and Pop2, homologues of budding yeast Cdc4 and human Fbw7, are responsible for Cig2 instability. Pop1 binds Cig2 in vivo. An in vitro binding assay shows that an internal 93 amino acid residues comprising a part of the cyclin box are necessary and sufficient for this binding. Cig2 phosphorylation is also required for interaction with Pop1. We previously showed that transcriptional oscillation of cig2(+) requires Pop1 and Pop2 function. SCF(Pop1/Pop2) therefore regulates Cig2 levels in a dual manner, transcriptionally and post-translationally. Our results also highlight a collaborative action of the APC/C and the SCF toward the common substrate Cig2. This type of composite degradation control may be more general as the regulatory mechanism in other complex systems.
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PMID:Requirement of the SCFPop1/Pop2 Ubiquitin Ligase for Degradation of the Fission Yeast S Phase Cyclin Cig2. 1497 Feb 37


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