An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid
| LEADER | caa a22 4500 | ||
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| 001 | 528785087 | ||
| 005 | 20190713030951.0 | ||
| 007 | cr unu---uuuuu | ||
| 008 | 180924s2012 xx s 000 0 eng | ||
| 024 | 7 | 0 | |a 10.3929/ethz-b-000062260 |2 doi |
| 024 | 7 | 0 | |a 10.1038/ncomms1680 |2 doi |
| 035 | |a (ETHRESEARCH)oai:www.research-collecti.ethz.ch:20.500.11850/62260 | ||
| 245 | 0 | 3 | |a An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid |h [Elektronische Daten] |c [Marc De la Roche, Trevor J. Rutherford, Deepti Gupta, Dmitry B. Veprintsev, Barbara Saxty, Stefan M. Freund, Mariann Bienz] |
| 246 | 0 | |a Nat Commun | |
| 506 | |a Open access |2 ethresearch | ||
| 520 | 3 | |a Wnt/β-catenin signalling controls development and tissue homeostasis. Moreover, activated β-catenin can be oncogenic and, notably, drives colorectal cancer. Inhibiting oncogenic β-catenin has proven a formidable challenge. Here we design a screen for small-molecule inhibitors of β-catenin's binding to its cofactor BCL9, and discover five related natural compounds, including carnosic acid from rosemary, which attenuates transcriptional β-catenin outputs in colorectal cancer cells. Evidence from NMR and analytical ultracentrifugation demonstrates that the carnosic acid response requires an intrinsically labile α-helix (H1) amino-terminally abutting the BCL9-binding site in β-catenin. Similarly, in colorectal cancer cells with hyperactive β-catenin signalling, carnosic acid targets predominantly the transcriptionally active ('oncogenic') form of β-catenin for proteasomal degradation in an H1-dependent manner. Hence, H1 is an 'Achilles' Heel' of β-catenin, which can be exploited for destabilization of oncogenic β-catenin by small molecules, providing proof-of-principle for a new strategy for developing direct inhibitors of oncogenic β-catenin. | |
| 540 | |a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported |u http://creativecommons.org/licenses/by-nc-nd/3.0 |2 ethresearch | ||
| 700 | 1 | |a De la Roche |D Marc |e joint author | |
| 700 | 1 | |a Rutherford |D Trevor J. |e joint author | |
| 700 | 1 | |a Gupta |D Deepti |e joint author | |
| 700 | 1 | |a Veprintsev |D Dmitry B. |e joint author | |
| 700 | 1 | |a Saxty |D Barbara |e joint author | |
| 700 | 1 | |a Freund |D Stefan M. |e joint author | |
| 700 | 1 | |a Bienz |D Mariann |e joint author | |
| 773 | 0 | |t Nature Communications |d London : Nature Publishing Group |g 3, p. 680 |x 2041-1723 | |
| 856 | 4 | 0 | |u http://hdl.handle.net/20.500.11850/62260 |q text/html |z WWW-Backlink auf das Repository (Open access) |
| 908 | |D 1 |a Journal Article |2 ethresearch | ||
| 950 | |B ETHRESEARCH |P 856 |E 40 |u http://hdl.handle.net/20.500.11850/62260 |q text/html |z WWW-Backlink auf das Repository (Open access) | ||
| 950 | |B ETHRESEARCH |P 700 |E 1- |a De la Roche |D Marc |e joint author | ||
| 950 | |B ETHRESEARCH |P 700 |E 1- |a Rutherford |D Trevor J. |e joint author | ||
| 950 | |B ETHRESEARCH |P 700 |E 1- |a Gupta |D Deepti |e joint author | ||
| 950 | |B ETHRESEARCH |P 700 |E 1- |a Veprintsev |D Dmitry B. |e joint author | ||
| 950 | |B ETHRESEARCH |P 700 |E 1- |a Saxty |D Barbara |e joint author | ||
| 950 | |B ETHRESEARCH |P 700 |E 1- |a Freund |D Stefan M. |e joint author | ||
| 950 | |B ETHRESEARCH |P 700 |E 1- |a Bienz |D Mariann |e joint author | ||
| 950 | |B ETHRESEARCH |P 773 |E 0- |t Nature Communications |d London : Nature Publishing Group |g 3, p. 680 |x 2041-1723 | ||
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 949 | |B ETHRESEARCH |F ETHRESEARCH |b ETHRESEARCH |j Journal Article |c Open access | ||