{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T12:50:29Z","timestamp":1762865429335,"version":"build-2065373602"},"reference-count":31,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2008,8,29]],"date-time":"2008-08-29T00:00:00Z","timestamp":1219968000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2008,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>FOXO proteins are direct targets of PI3K\/Akt signaling and they integrate the signals of several other transduction pathways at the transcriptional level. FOXO transcription factors are involved in normal cell homeostasis and neoplasia, and they are regulated by multiple post\u2010transcriptional modifications. In cancer research, the regulation of the FOXO factors is receiving increasing attention as their activation has been linked to cell\u2010cycle arrest and apoptosis. Hence, FOXO proteins have been proposed to act as tumor suppressors. Here, we applied a chemical biology approach to study the mechanisms that influence the intracellular localization of the FOXO family member FOXO3a. We established a high\u2010throughput cellular\u2010imaging assay that monitors the nuclear\u2013cytoplasmic translocation of a GFP\u2013FOXO3a fusion protein in tumor cells. Nuclear accumulation of fluorescent signals upon treatment with the known PI3K inhibitors LY294002, wortmannin, PIK\u201075, and PI\u2010103 was dose dependent and agreed well with the IC<jats:sub>50<\/jats:sub> values reported for PI3K\u03b1 inhibition in vitro. Additionally, we identified 17 compounds from a panel of 73 low\u2010molecular\u2010weight compounds capable of inducing the nuclear accumulation of GFP\u2013FOXO. These compounds include chemicals known to interfere with components of the PI3K\/Akt signaling pathway, as well as with nuclear export and Ca<jats:sup>2+<\/jats:sup>\/calmodulin (CaM)\u2010dependent signaling events. Interestingly, the therapeutic agent vinblastine induced efficient nuclear translocation of the FOXO reporter protein. Our data illustrate the potential of chemical genetics when combined with robust and sensitive high\u2010content\u2010screening technology.<\/jats:p>","DOI":"10.1002\/cbic.200800255","type":"journal-article","created":{"date-parts":[[2008,8,29]],"date-time":"2008-08-29T06:01:13Z","timestamp":1219989673000},"page":"2229-2237","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Chemical Genetic Analysis of FOXO Nuclear\u2013Cytoplasmic Shuttling by Using Image\u2010Based Cell Screening"],"prefix":"10.1002","volume":"9","author":[{"given":"Fabian","family":"Zanella","sequence":"first","affiliation":[]},{"given":"Aranzaz\u00fa","family":"Rosado","sequence":"additional","affiliation":[]},{"given":"Beatriz","family":"Garc\u00eda","sequence":"additional","affiliation":[]},{"given":"Amancio","family":"Carnero","sequence":"additional","affiliation":[]},{"given":"Wolfgang","family":"Link","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2008,9,17]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5261"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80595-4"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.10.5024"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.7.2025-2036.2002"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.23.8969-8982.2000"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.5.2181-2189.2004"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00302-2"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00086-7"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.12.029"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2190"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20040167"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.03.046"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200409117"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600476"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1469"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412357200"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20070003"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20070797"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.2522"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00439.2003"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(03)00255-7"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1130512"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(03)00303-9"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1089\/adt.2007.058"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1159\/000137808"},{"key":"e_1_2_6_26_2","first-page":"1667","volume":"63","author":"Sawyer 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