title: Regulation of hedgehog signaling by Myc-interacting zinc finger protein 1, Miz1.
abstract: Smoothened (Smo) mediated Hedgehog (Hh) signaling plays an essential role in regulating embryonic development and postnatal tissue homeostasis. Aberrant activation of the Hh pathway contributes to the formation and progression of various cancers. In vertebrates, however, key regulatory mechanisms responsible for transducing signals from Smo to the nucleus remain to be delineated. Here, we report the identification of Myc-interacting Zinc finger protein 1 (Miz1) as a Smo and Gli2 binding protein that positively regulates Hh signaling. Overexpression of Miz1 increases Gli luciferase reporter activity, whereas knockdown of endogenous Miz1 has the opposite effect. Activation of Smo induces translocation of Miz1 to the primary cilia together with Smo and Gli2. Furthermore, Miz1 is localized to the nucleus upon Hh activation in a Smo-dependent manner, and loss of Miz1 prevents the nuclear translocation of Gli2. More importantly, silencing Miz1 expression inhibits cell proliferation in vitro and the growth of Hh-driven medulloblastoma tumors allografted in SCID mice. Taken together, these results identify Miz1 as a novel regulator in the Hh pathway that plays an important role in mediating Smo-dependent oncogenic signaling.
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: Jiuyi
authors.initials: J
authors.lastname: Lu
authors.forename: Minyong
authors.initials: M
authors.lastname: Chen
authors.forename: Xiu-Rong
authors.initials: XR
authors.lastname: Ren
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Wang
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
authors.forename: Larry
authors.initials: L
authors.lastname: Barak
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002923:Cilia / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008527:Medulloblastoma / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000502:physiology*; D009857:Oncogenes; D011485:Protein Binding; D050828:Protein Inhibitors of Activated STAT / Q000502:physiology*; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D044767:Ubiquitin-Protein Ligases; D000075746:Zinc Finger Protein Gli2
chemical_list: C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2; C485521:Miz1 protein, mouse; D044767:Ubiquitin-Protein Ligases