Identification of p18 INK4c as a tumor suppressor gene in glioblastoma multiforme.
Genomic alterations leading to aberrant activation of cyclin/cyclin-dependent kinase (cdk) complexes drive the pathogenesis of many common human tumor types. In the case of glioblastoma multiforme (GBM), these alterations are most commonly due to homozygous deletion of p16(INK4a) and less commonly due to genomic amplifications of individual genes encoding cyclins or cdks. Here, we describe deletion of the p18(INK4c) cdk inhibitor as a novel genetic alteration driving the pathogenesis of GBM. Deletions of p18(INK4c) often occurred in tumors also harboring homozygous deletions of p16(INK4a). Expression of p18(INK4c) was completely absent in 43% of GBM primary tumors studied by immunohistochemistry. Lentiviral reconstitution of p18(INK4c) expression at physiologic levels in p18(INK4c)-deficient but not p18(INK4c)-proficient GBM cells led to senescence-like G(1) cell cycle arrest. These studies identify p18(INK4c) as a GBM tumor suppressor gene, revealing an additional mechanism leading to aberrant activation of cyclin/cdk complexes in this terrible malignancy.
Solomon
David A
DA
Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia 20057, USA.
Kim
Jung-Sik
JS
Jenkins
Sultan
S
Ressom
Habtom
H
Huang
Michael
M
Coppa
Nicholas
N
Mabanta
Lauren
L
Bigner
Darell
D
Yan
Hai
H
Jean
Walter
W
Waldman
Todd
T
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D014183:Transplantation, Heterologous
D050763:Cyclin-Dependent Kinase Inhibitor p18; D004273:DNA, Neoplasm