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Feedback circuit among INK4 tumor suppressors constrains human glioblastoma development.

We have developed a nonheuristic genome topography scan (GTS) algorithm to characterize the patterns of genomic alterations in human glioblastoma (GBM), identifying frequent p18(INK4C) and p16(INK4A) codeletion. Functional reconstitution of p18(INK4C) in GBM cells null for both p16(INK4A) and p18(INK4C) resulted in impaired cell-cycle progression and tumorigenic potential. Conversely, RNAi-mediated depletion of p18(INK4C) in p16(INK4A)-deficient primary astrocytes or established GBM cells enhanced tumorigenicity in vitro and in vivo. Furthermore, acute suppression of p16(INK4A) in primary astrocytes induced a concomitant increase in p18(INK4C). Together, these findings uncover a feedback regulatory circuit in the astrocytic lineage and demonstrate a bona fide tumor suppressor role for p18(INK4C) in human GBM wherein it functions cooperatively with other INK4 family members to constrain inappropriate proliferation.

Pubmed ID: 18394558


  • Wiedemeyer R
  • Brennan C
  • Heffernan TP
  • Xiao Y
  • Mahoney J
  • Protopopov A
  • Zheng H
  • Bignell G
  • Furnari F
  • Cavenee WK
  • Hahn WC
  • Ichimura K
  • Collins VP
  • Chu GC
  • Stratton MR
  • Ligon KL
  • Futreal PA
  • Chin L


Cancer cell

Publication Data

April 8, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: P01 CA095616
  • Agency: NCI NIH HHS, Id: P01 CA095616-060004
  • Agency: NCI NIH HHS, Id: P01 CA095616-070004
  • Agency: NCI NIH HHS, Id: P01CA95616
  • Agency: NCI NIH HHS, Id: R01 CA099041
  • Agency: NCI NIH HHS, Id: R01 CA099041-05
  • Agency: NCI NIH HHS, Id: R01CA99041
  • Agency: NIAMS NIH HHS, Id: T32 AR007098
  • Agency: Wellcome Trust, Id:

Mesh Terms

  • Animals
  • Astrocytes
  • Cell Line, Tumor
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18
  • Feedback, Physiological
  • Gene Deletion
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic
  • Genome, Human
  • Glioblastoma
  • Humans
  • Mice
  • Up-Regulation