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Sci. Signal., 25 January 2011
Vol. 4, Issue 157, p. ra4
[DOI: 10.1126/scisignal.2001225]
RESEARCH ARTICLES
Genome-Wide RNAi Screen Reveals Disease-Associated Genes That Are Common to Hedgehog and Wnt Signaling
Leni S. Jacob1,
Xiaofeng Wu1,
Michael E. Dodge1,
Chih-Wei Fan1,
Ozlem Kulak1,
Baozhi Chen1,
Wei Tang1*,
Baolin Wang2,3,
James F. Amatruda4,5, and
Lawrence Lum1
1 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 2 Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA. 3 Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA. 4 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 5 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
* Present address: BioDuro Co. Ltd., No. 29 Building, Life Science Park Road, Changping District, 102206 Beijing, People’s Republic of China.
Abstract:
The Hedgehog (Hh) and Wnt signal transduction pathways are master regulators of embryogenesis and tissue renewal and represent anticancer therapeutic targets. Using genome-wide RNA interference screening in murine cultured cells, we established previously unknown associations between these signaling pathways and genes linked to developmental malformations, diseases of premature tissue degeneration, and cancer. We identified functions in both pathways for the multitasking kinase Stk11 (also known as Lkb1), a tumor suppressor implicated in lung and cervical cancers. We found that Stk11 loss resulted in disassembly of the primary cilium, a cellular organizing center for Hh pathway components, thus dampening Hh signaling. Loss of Stk11 also induced aberrant signaling through the Wnt pathway. Chemicals that targeted the Wnt acyltransferase Porcupine or that restored primary cilia length by inhibiting the tubulin deacetylase HDAC6 (histone deacetylase 6) countered deviant pathway activities driven by Stk11 loss. Our study demonstrates that Stk11 is a critical mediator in both the Hh and the Wnt pathways, and our approach provides a platform to support the development of targeted therapeutic strategies.
To whom correspondence should be addressed. E-mail: lawrence.lum{at}UTSouthwestern.edu
Citation: L. S. Jacob, X. Wu, M. E. Dodge, C.-W. Fan, O. Kulak, B. Chen, W. Tang, B. Wang, J. F. Amatruda, L. Lum, Genome-Wide RNAi Screen Reveals Disease-Associated Genes That Are Common to Hedgehog and Wnt Signaling. Sci. Signal.4, ra4 (2011).
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