title: Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis.
abstract: Abnormal activation of Hedgehog (Hh) signaling leads to basal cell carcinoma (BCC) of the skin, the most common human cancer. Gli2, the major transcriptional activator of Hh signaling, is essential for hair follicle development and its overexpression in epidermis induces BCC formation and maintains tumor growth. Despite its importance in skin development and tumorigenesis, little is known about the molecular regulation of Gli2. Sufu and Kif7 are two evolutionarily conserved regulators of Gli transcription factors. Here, we show that Sufu and Kif7 regulate Gli2 through distinct mechanisms in keratinocytes. Sufu restricts the activity of Gli2 through cytoplasmic sequestration. Kif7 possesses Sufu-dependent and -independent regulatory functions in Hh signaling: while it promotes Hh pathway activity through the dissociation of Sufu-Gli2 complex, it also contributes to the repression of Hh target genes in the absence of Sufu. Deletion of both Sufu and Kif7 in embryonic skin leads to complete loss of follicular fate. Importantly, although inactivation of Sufu or Kif7 alone in adult epidermis cannot promote BCC formation, their simultaneous deletion induces BCC. These studies establish Sufu and Kif7 as crucial components in the regulation of Gli2 localization and activity, and illustrate their overlapping functions in skin development and tumor suppression.
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Zhu Juan
authors.initials: ZJ
authors.lastname: Li
authors.forename: Erica
authors.initials: E
authors.lastname: Nieuwenhuis
authors.forename: Weilun
authors.initials: W
authors.lastname: Nien
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zhang
authors.forename: Vijitha
authors.initials: V
authors.lastname: Puviindran
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Wainwright
authors.forename: Peter C W
authors.initials: PC
authors.lastname: Kim
authors.forename: Chi-chung
authors.initials: CC
authors.lastname: Hui
mesh_terms: D000818:Animals; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D003593:Cytoplasm; D018859:Hair Follicle / Q000196:embryology; D053823:Hedgehog Proteins; D015603:Keratinocytes / Q000378:metabolism*; D016547:Kinesins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000196:embryology*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D000075746:Zinc Finger Protein Gli2
chemical_list: C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D012097:Repressor Proteins; C490763:Sufu protein, mouse; D000075746:Zinc Finger Protein Gli2; C543639:Kif7 protein, mouse; D016547:Kinesins