title: Feedback circuit among INK4 tumor suppressors constrains human glioblastoma development.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ruprecht
authors.initials: R
authors.lastname: Wiedemeyer
authors.forename: Cameron
authors.initials: C
authors.lastname: Brennan
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffernan
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xiao
authors.forename: John
authors.initials: J
authors.lastname: Mahoney
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zheng
authors.forename: Graham
authors.initials: G
authors.lastname: Bignell
authors.forename: Frank
authors.initials: F
authors.lastname: Furnari
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Koichi
authors.initials: K
authors.lastname: Ichimura
authors.forename: V Peter
authors.initials: VP
authors.lastname: Collins
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Chu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
mesh_terms: 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
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18