Molecular Mechanisms of Mammalian Hedgehog Signal Transduction

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The long-term goal of this study is to understand the molecular mechanism of mammalian Hedgehog (Hh) signal transduction. Aberrant Hh signaling has been associated with various human cancers and birth defects. Recent evidence indicates that several aspects of Hh signaling are not conserved between invertebrates and vertebrates. Not only have the roles of some of the main players changed in vertebrates, but also their genetic interactions and the mode of signal transduction have been modified. Further, primary cilia appear to play a major role in mammalian and not Drosophila Hh signaling. These findings highlight the importance of elucidating the functions of mammalian Hh pathway components directly in order to further understand vertebrate Hh signal transduction. This proposal focuses on one critical player in mammalian Hh signal transduction, Suppressor of Fused (Sufu), and will define the mechanism of Sufu in regulating the functions of Gli transcription factors, the sole mediators of Hh signaling during mammalian development. We propose the following specific aims: 1) Define the role of Sufu in controlling ciliary localization of Gli2. 2) Elucidate the molecular mechanism of Sufu-mediated Gli3 protein stabilization. 3) Delineate the requirement of primary cilia in Sufu- or SPOP-mediated Gli protein function. 4) Test the hypothesis that Sufu interacts with Kif7, a kinesin family member, in modulating mammalian Hh signaling. A combination of cell-based assays, genetic studies using knockout mice and protein biochemistry will be employed to address these central issues. These studies will provide new mechanistic insights into how the mammalian Hh signal is transduced in responsive cells 7. PUBLIC HEALTH RELEVANCE: Aberrant Hedgehog (Hh) signaling is associated with cancers and birth defects. Elucidating how the Hh signal is transduced is critical to understanding the underlying mechanisms of Hh-related diseases as well as identifying potential targets for diagnosis and rational therapies.