| Title | Feedback circuit among INK4 tumor suppressors constrains human glioblastoma development. |
| Publication Type | Journal Article |
| Year of Publication | 2008 |
| Authors | Wiedemeyer R, Brennan C, Heffernan TP, Xiao Y, Mahoney J, Protopopov A, Zheng H, Bignell G, Furnari F, Cavenee WK, Hahn WC, Ichimura K, V Collins P, Chu GC, Stratton MR, Ligon KL, P Futreal A, Chin L |
| Journal | Cancer Cell |
| Volume | 13 |
| Issue | 4 |
| Pagination | 355-64 |
| Date Published | 2008 Apr |
| ISSN | 1878-3686 |
| Keywords | Animals, Astrocytes, Cell Line, Tumor, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p18, Feedback, Physiological, Gene Deletion, Gene Dosage, Gene Expression Regulation, Neoplastic, Genome, Human, Glioblastoma, Humans, Mice, Up-Regulation |
| 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. |
| DOI | 10.1016/j.ccr.2008.02.010 |
| Alternate Journal | Cancer Cell |
| PubMed ID | 18394558 |
| Grant List | P01CA95616 / CA / NCI NIH HHS / United States R01CA99041 / CA / NCI NIH HHS / United States / WT_ / Wellcome Trust / United Kingdom |
Related Faculty:
Hongwu Zheng, Ph.D.