We are interested in the involvement of the Wnt signaling pathway in cellular proliferation and differentiation—in particular, the differential coactivator usage, and the mechanisms governing differential coactivator usage to control gene expression.
Despite their high degree of homology and similar patterns of expression, CBP and p300 play unique and distinct roles in gene regulation. Our chemogenomic studies with ICG-001, a specific CBP/beta-catenin antagonist, present clear evidence that CBP and p300 have distinct functions in regulating the transcription of Wnt/beta-catenin genes. We have developed a model, which proposes that TCF/beta-catenin/CBP-mediated transcription is critical for proliferation without differentiation (e.g. in cancer and stem cells) (Fig.1, left arm of the pathway). However, the switch of coactivators by the TCF/beta-catenin complex is the essential first step in the initiation of differentiation. The TCF/beta-catenin/p300 complex then drives the transcription of the Wnt/beta-catenin regulated genes associated with normal cellular differentiation (Fig. 1, right arm). Aberrant regulation of the balance between these two related transcriptional programs may be associated with a wide array of diseases.
The major focus of the lab is on the role of Wnt signaling in development, disease and aging. Using proprietary pharmacologic tools that our lab has developed, which modulate the Wnt signaling cascade, we are investigating the role of Wnt signaling in embryonic stem cells (both proliferation and differentiation), somatic stem cells under both physiologic and pathologic conditions (including cancer, fibrosis, chronic inflammatory disease, neurodegeneration, muscle injury, osteoporosis and aging). The lab is also involved in collaborative efforts to develop chemical reprogramming. A range of techniques are applied to these problems including HTS screening (of both siRNA and small molecules), cell and molecular biology, proteomics and animal models.