Wiedemeyer, RuprechtBrennan, CameronHeffernan, Timothy P.Xiao, YonghongMahoney, JohnProtopopov, AlexeiZheng, HongwuBignell, GrahamFurnari, FrankCavenee, Webster K.Hahn, WilliamIchimura, KoichiCollins, Peter V.Chu, Gerald C.Stratton, Michael R.Ligon, KeithFutreal, Andrew P.Chin, Lynda2011-04-182008Wiedemeyer, Ruprecht, Cameron Brennan, Timothy P. Heffernan, Yonghong Xiao, John Mahoney, Alexei Protopopov, Hongwu Zheng, et al. 2008. Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma Development. Cancer Cell 13(4): 355-364.1535-6108http://nrs.harvard.edu/urn-3:HUL.InstRepos:4853393We 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 p18INK4C 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.en-UScell cycleJournal Article2011-04-1810.1016/j.ccr.2008.02.010