title: Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.
abstract: The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. By screening a diverse synthetic chemical library, we have discovered two new classes of small molecules that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/beta-catenin pathway activity. With these small molecules, we establish a chemical genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/beta-catenin pathway response in vivo, and we establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chemically tractable additionally contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: Baozhi
authors.initials: B
authors.lastname: Chen
authors.forename: Michael E
authors.initials: ME
authors.lastname: Dodge
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Jianming
authors.initials: J
authors.lastname: Lu
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Ma
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Fan
authors.forename: Shuguang
authors.initials: S
authors.lastname: Wei
authors.forename: Wayne
authors.initials: W
authors.lastname: Hao
authors.forename: Jessica
authors.initials: J
authors.lastname: Kilgore
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.forename: Michael G
authors.initials: MG
authors.lastname: Roth
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
authors.forename: Chuo
authors.initials: C
authors.lastname: Chen
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lum
mesh_terms: D060466:Axin Protein; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism*; D012038:Regeneration; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology
chemical_list: D060466:Axin Protein; D012097:Repressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin