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.
Wiedemeyer
Ruprecht
R
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Brennan
Cameron
C
Heffernan
Timothy P
TP
Xiao
Yonghong
Y
Mahoney
John
J
Protopopov
Alexei
A
Zheng
Hongwu
H
Bignell
Graham
G
Furnari
Frank
F
Cavenee
Webster K
WK
Hahn
William C
WC
Ichimura
Koichi
K
Collins
V Peter
VP
Chu
Gerald C
GC
Stratton
Michael R
MR
Ligon
Keith L
KL
Futreal
P Andrew
PA
Chin
Lynda
L
D000818:Animals; D001253:Astrocytes / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism*; D025461:Feedback, Physiological; D017353:Gene Deletion; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D015854:Up-Regulation / Q000235:genetics
D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18