Feedback circuit among INK4 tumor suppressors constrains human glioblastoma development Journal Article
| Authors: | Wiedemeyer, R.; Brennan, C.; Heffernan, T. P.; Xiao, Y.; Mahoney, J.; Protopopov, A.; Zheng, H.; Bignell, G.; Furnari, F.; Cavenee, W. K.; Hahn, W. C.; Ichimura, K.; Collins, V. P.; Chu, G. C.; Stratton, M. R.; Ligon, K. L.; Futreal, P. A.; Chin, L. |
| Article 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 p18INK4C and p16INK4A codeletion. Functional reconstitution of p18INK4C in GBM cells null for both p16INK4A and p18INK4C resulted in impaired cell-cycle progression and tumorigenic potential. Conversely, RNAi-mediated depletion of p18INK4C in p16INK4A-deficient primary astrocytes or established GBM cells enhanced tumorigenicity in vitro and in vivo. Furthermore, acute suppression of p16INK4A in primary astrocytes induced a concomitant increase in p18INK4C. Together, these findings uncover a feedback regulatory circuit in the astrocytic lineage and demonstrate a bona fide tumor suppressor role for p18INK4C in human GBM wherein it functions cooperatively with other INK4 family members to constrain inappropriate proliferation. © 2008 Elsevier Inc. All rights reserved. |
| Keywords: | controlled study; human cell; gene deletion; protein function; cell proliferation; animals; mice; cells, cultured; cell cycle progression; astrocyte; rna interference; in vivo study; in vitro study; cell line, tumor; carcinogenesis; cell lineage; cancer inhibition; gene expression regulation, neoplastic; algorithm; gene identification; glioblastoma; gene repression; tumor cell; genomics; cellcycle; feedback system; cyclin dependent kinase inhibitor 2a; cyclin-dependent kinase inhibitor p16; gene dosage; up-regulation; genome, human; cyclin dependent kinase inhibitor 2c; astrocytes; feedback, biochemical; cyclin-dependent kinase inhibitor p18 |
| Journal Title: | Cancer Cell |
| Volume: | 13 |
| Issue: | 4 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2008-04-08 |
| Start Page: | 355 |
| End Page: | 364 |
| Language: | English |
| DOI: | 10.1016/j.ccr.2008.02.010 |
| PUBMED: | 18394558 |
| PROVIDER: | scopus |
| PMCID: | PMC2292238 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 40" - "Export Date: 17 November 2011" - "CODEN: CCAEC" - "Source: Scopus" |
