Wnt/β-catenin signaling is critically involved in metazoan development, stem cell maintenance and human disease. Using Xenopus laevis egg extract to screen for compounds that both stabilize Axin and promote β-catenin turnover, we identified an FDA-approved drug, pyrvinium, as a potent inhibitor of Wnt signaling (EC50 of ~10 nM). We show pyrvinium binds all casein kinase 1 (CK1) family members in vitro at low nanomolar concentrations and pyrvinium selectively potentiates casein kinase 1α (CK1α) kinase activity. CK1α knockdown abrogates the effects of pyrvinium on the Wnt pathway. In addition to its effects on Axin and β-catenin levels, pyrvinium promotes degradation of Pygopus, a Wnt transcriptional component. Pyrvinium treatment of colon cancer cells with mutation of the gene for adenomatous polyposis coli (APC) or β-catenin inhibits both Wnt signaling and proliferation. Our findings reveal allosteric activation of CK1α as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway.

We attempt to provide a more nuanced view of the relationship between corporate social responsibility (CSR) and firm financial performance using a competitive-action perspective. We argue that competitive action should be considered as an important contingency that determines the effects of CSR activities on firm financial performance. Using data for 113 publicly listed U.S. firms in the software industry between 2000 and 2005, we found that socially responsible activities (positive CSR) enhance firm financial performance when the firm’s competitive-action level is high, whereas socially irresponsible activities (negative CSR) actually improve firm financial performance when the competitive-action level is low. By introducing competitive action as an important contingency, this study contributes to the literature on CSR and strategic management.

No abstract

No abstract

Activators of M 1 muscarinic acetylcholine receptors (mAChRs) may provide novel treatments for schizophrenia and Alzheimer's disease. Unfortunately, the development of M 1 -active compounds has resulted in nonselective activation of the highly related M 2 to M 5 mAChR subtypes, which results in doselimiting side effects. Using a functional screening approach, we identified several novel ligands that potentiated agonist activation of M 1 with low micromolar potencies and induced 5-fold or greater leftward shifts of the acetylcholine (ACh) concentrationresponse curve. These ligands did not compete for binding at the ACh binding site, indicating that they modulate receptor activity by binding to allosteric sites. The two most selective compounds, cyclopentyl 1,progressive shifts in ACh affinity at M 1 that were consistent with their effects in a functional assay, suggesting that the mechanism for enhancement of M 1 activity by these compounds is by increasing agonist affinity. These compounds were strikingly different, however, in their ability to potentiate responses at a mutant M 1 receptor with decreased affinity for ACh and in their ability to affect responses of the allosteric M 1 agonist, 1-[1Ј-(2-tolyl)-1,4Ј-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one. Furthermore, these two compounds were distinct in their abilities to potentiate M 1 -mediated activation of phosphoinositide hydrolysis and phospholipase D. The discovery of multiple structurally distinct positive allosteric modulators of M 1 is an exciting advance in establishing the potential of allosteric modulators for selective activation of this receptor. These data also suggest that structurally diverse M 1 potentiators may act by distinct mechanisms and differentially regulate receptor coupling to downstream signaling pathways.The psychotic and cognitive symptoms of neuropsychiatric disorders such as schizophrenia and Alzheimer's disease (AD) remain serious unmet medical challenges. Patients with schizophrenia exhibit a constellation of symptoms that include positive, negative, and cognitive symptom clusters. Although current antipsychotic agents are effective in reducing positive symptoms such as hallucinations and delusions in most patients, negative symptoms such as anhedonia and blunted affect, as well as deficits in cognitive function, are not effectively treated with current medications (Vohora, 2007). In addition to the unmet medical needs of schizophrenia, the devastating cognitive and neuropsychiatric symptoms characteristic of AD present urgent needs for new therapeutic interventions (Saddichha and Pandey, 2008).