1. Primary cilium-dependent and -independent Hedgehog signaling inhibits p16(INK4A).
- Author
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Bishop CL, Bergin AM, Fessart D, Borgdorff V, Hatzimasoura E, Garbe JC, Stampfer MR, Koh J, and Beach DH
- Subjects
- Female, Genome, Human genetics, Humans, Protein Interaction Mapping, RNA, Small Interfering metabolism, Young Adult, Zinc Finger Protein Gli2, Cilia metabolism, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Hedgehog Proteins metabolism, Kruppel-Like Transcription Factors metabolism, Nuclear Proteins metabolism, Signal Transduction
- 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., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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