Functional Genomics Based Interrogation of Cell-Fate Determination Pathways

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Title: Functional Genomics Based Interrogation of Cell-Fate Determination Pathways
Author: Jacob, Leni Susan
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 , I established previously unknown associations between these signaling pathways and genes linked to developmental malformations , diseases of premature tissue degeneration , and cancer . I identified functions in both pathways for the multitasking kinase Stk11 (also known as Lkb1 ) , a tumor suppressor implicated in lung and cervical cancers . 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 . My study demonstrates that Stk11 is a critical mediator in both the Hh and the Wnt pathways , and that functional genomics based approaches to dissecting cell -fate determination pathways may support the development of targeted therapeutic strategies .
URI: http : / /hdl .handle .net /2152 .5 /884
Date: 2011-08-26

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Functional Genomics Based Interrogation of Cell-Fate Determination Pathways. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /884 .

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