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PMID: 18394558 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Feedback circuit among INK4 tumor suppressors constrains human glioblastoma development.

Cancer cell ·Vol. 13 ·No. 4 ·2008-04-00 ·Pages 355-64

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

Abstract

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.

MeSH Terms
Animals Astrocytes/pathology Cell Line, Tumor Cells, Cultured Cyclin-Dependent Kinase Inhibitor p16/metabolism Cyclin-Dependent Kinase Inhibitor p18/metabolism Feedback, Physiological Gene Deletion Gene Dosage Gene Expression Regulation, Neoplastic Genome, Human Glioblastoma/genetics,metabolism,pathology Humans Mice Up-Regulation/genetics
Chemicals
Cyclin-Dependent Kinase Inhibitor p16 Cyclin-Dependent Kinase Inhibitor p18
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Wiedemeyer Ruprecht
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Brennan Cameron
Heffernan Timothy P
Xiao Yonghong
Mahoney John
Protopopov Alexei
Zheng Hongwu
Bignell Graham
Furnari Frank
Cavenee Webster K
Hahn William C
Ichimura Koichi
Collins V Peter
Chu Gerald C
Stratton Michael R
Ligon Keith L
Futreal P Andrew
Chin Lynda
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2008.02.010
Published
2008-04-00
Pages
355-64
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2292238
Subset
IM
Grants
Wellcome Trust · United Kingdom
NCI NIH HHS · P01 CA095616-060004 · United States
NCI NIH HHS · R01 CA099041 · United States
NCI NIH HHS · P01 CA095616 · United States
NCI NIH HHS · P01CA95616 · United States
NCI NIH HHS · R01CA99041 · United States
NCI NIH HHS · P01 CA095616-070004 · United States
NCI NIH HHS · R01 CA099041-05 · United States
NIAMS NIH HHS · T32 AR007098 · United States
Databases
GEO
GSE9200
External Links
PubMed source DOI: 10.1016/j.ccr.2008.02.010 PMC Full Text View journal details
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