title: Primary cilium-dependent and -independent Hedgehog signaling inhibits p16(INK4A).
abstract: In a genome-wide siRNA analysis of p16(INK4a) (p16) modulators, we identify the Hedgehog (Hh) pathway component SUFU and formally demonstrate that Hh signaling promotes mitogenesis by suppression of p16. A fragment of the Hh-responsive GLI2 transcription factor directly binds and inhibits the p16 promoter and senescence is associated with the loss of nuclear GLI2. Hh components partially reside in the primary cilium (PC), and the small fraction of cells in mass culture that elaborate a PC have the lowest expression of p16. Suppression of p16 is effected by both PC-dependent and -independent routes, and ablation of p16 renders cells insensitive to an Hh inhibitor and increases PC formation. These results directly link a well-established developmental mitogenic pathway with a key tumor suppressor and contribute to the molecular understanding of replicative senescence, Hh-mediated oncogenesis, and potentially the role of p16 in aging.
authors.affiliation: Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK. c.l.bishop@qmul.ac.uk
authors.forename: Cleo L
authors.initials: CL
authors.lastname: Bishop
authors.forename: Ann-Marie H
authors.initials: AM
authors.lastname: Bergin
authors.forename: Delphine
authors.initials: D
authors.lastname: Fessart
authors.forename: Viola
authors.initials: V
authors.lastname: Borgdorff
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hatzimasoura
authors.forename: James C
authors.initials: JC
authors.lastname: Garbe
authors.forename: Martha R
authors.initials: MR
authors.lastname: Stampfer
authors.forename: Jim
authors.initials: J
authors.lastname: Koh
authors.forename: David H
authors.initials: DH
authors.lastname: Beach
mesh_terms: D002923:Cilia / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005260:Female; D015894:Genome, Human / Q000235:genetics; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D025941:Protein Interaction Mapping; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult; D000075746:Zinc Finger Protein Gli2
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000075746:Zinc Finger Protein Gli2