Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma Development

Ruprecht Wiedemeyer; Cameron Brennan; Timothy P. Heffernan; Yonghong Xiao; John Mahoney; Alexei Protopopov; Hongwu Zheng; Graham Bignell; Frank Furnari; Webster K. Cavenee; William C. Hahn; Koichi Ichimura; V. Peter Collins; Gerald C. Chu; Michael R. Stratton; Keith L. Ligon; P. Andrew Futreal; Lynda Chin

doi:10.1016/j.ccr.2008.02.010

Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma Development

Ruprecht Wiedemeyer, Cameron Brennan, Timothy P. Heffernan, Yonghong Xiao, John Mahoney, Alexei Protopopov, Hongwu Zheng, Graham Bignell, Frank Furnari, Webster K. Cavenee, William C. Hahn, Koichi Ichimura, V. Peter Collins, Gerald C. Chu, Michael R. Stratton, Keith L. Ligon, P. Andrew Futreal, Lynda Chin

Genomic Medicine

Research output: Contribution to journal › Article › peer-review

108 Scopus citations

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.

Original language	English (US)
Pages (from-to)	355-364
Number of pages	10
Journal	Cancer cell
Volume	13
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2008.02.010
State	Published - Apr 8 2008

Keywords

CELLCYCLE

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccr.2008.02.010

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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. (2008). Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma Development. Cancer cell, 13(4), 355-364. https://doi.org/10.1016/j.ccr.2008.02.010

Wiedemeyer, R, Brennan, C, Heffernan, TP, Xiao, Y, Mahoney, J, Protopopov, A, Zheng, H, Bignell, G, Furnari, F, Cavenee, WK, Hahn, WC, Ichimura, K, Collins, VP, Chu, GC, Stratton, MR, Ligon, KL, Futreal, PA & Chin, L 2008, 'Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma Development', Cancer cell, vol. 13, no. 4, pp. 355-364. https://doi.org/10.1016/j.ccr.2008.02.010

@article{a6e02445ec004de8a9f429086c5fbbac,

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.",

keywords = "CELLCYCLE",

author = "Ruprecht Wiedemeyer and Cameron Brennan and Heffernan, {Timothy P.} and Yonghong Xiao and John Mahoney and Alexei Protopopov and Hongwu Zheng and Graham Bignell and Frank Furnari and Cavenee, {Webster K.} and Hahn, {William C.} and Koichi Ichimura and Collins, {V. Peter} and Chu, {Gerald C.} and Stratton, {Michael R.} and Ligon, {Keith L.} and Futreal, {P. Andrew} and Lynda Chin",

note = "Funding Information: We thank Dr. Ron DePinho for critical reading of the manuscript, Dr. Christoph Geisen for the INK4A cDNA and the E2F expression vectors, Dr. Yue Xiong for the INK4C cDNA, and Thomas Santarius and Steven N. Quayle. Cell line resequencing was performed by the Cancer Genome Project at the Wellcome Trust Sanger Institute, UK. The genomic data were generated in the Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science at Dana-Farber Cancer Institute. R.W. is funded by a Mildred-Scheel fellowship (Deutsche Krebshilfe). ShRNA were provided from the RNAi Consortium at the Broad Institute. T.P.H. is funded by NIH T32 AR007098. P.A.F and M.R.S are funded by the Wellcome Trust. W.K.C. is a Fellow of the National Foundation for Cancer Research. This work is supported in part by NIH grants RO1CA99041 (L.C.) and P01CA95616 (W.K.C., F.F., W.C.H., K.L.L., C.B., and L.C.), as well as awards from Accelerate Brain Cancer Cure (to C.B.), the Goldhirsh Foundation (to F.F. and L.C.), and the Chris Elliot Foundation (to L.C.). ",

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doi = "10.1016/j.ccr.2008.02.010",

language = "English (US)",

volume = "13",

pages = "355--364",

journal = "Cancer cell",

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T1 - Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma Development

AU - Wiedemeyer, Ruprecht

AU - Brennan, Cameron

AU - Heffernan, Timothy P.

AU - Xiao, Yonghong

AU - Mahoney, John

AU - Protopopov, Alexei

AU - Zheng, Hongwu

AU - Bignell, Graham

AU - Furnari, Frank

AU - Cavenee, Webster K.

AU - Hahn, William C.

AU - Ichimura, Koichi

AU - Collins, V. Peter

AU - Chu, Gerald C.

AU - Stratton, Michael R.

AU - Ligon, Keith L.

AU - Futreal, P. Andrew

AU - Chin, Lynda

N1 - Funding Information: We thank Dr. Ron DePinho for critical reading of the manuscript, Dr. Christoph Geisen for the INK4A cDNA and the E2F expression vectors, Dr. Yue Xiong for the INK4C cDNA, and Thomas Santarius and Steven N. Quayle. Cell line resequencing was performed by the Cancer Genome Project at the Wellcome Trust Sanger Institute, UK. The genomic data were generated in the Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science at Dana-Farber Cancer Institute. R.W. is funded by a Mildred-Scheel fellowship (Deutsche Krebshilfe). ShRNA were provided from the RNAi Consortium at the Broad Institute. T.P.H. is funded by NIH T32 AR007098. P.A.F and M.R.S are funded by the Wellcome Trust. W.K.C. is a Fellow of the National Foundation for Cancer Research. This work is supported in part by NIH grants RO1CA99041 (L.C.) and P01CA95616 (W.K.C., F.F., W.C.H., K.L.L., C.B., and L.C.), as well as awards from Accelerate Brain Cancer Cure (to C.B.), the Goldhirsh Foundation (to F.F. and L.C.), and the Chris Elliot Foundation (to L.C.).

PY - 2008/4/8

Y1 - 2008/4/8

N2 - 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.

AB - 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.

KW - CELLCYCLE

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U2 - 10.1016/j.ccr.2008.02.010

DO - 10.1016/j.ccr.2008.02.010

M3 - Article

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AN - SCOPUS:41449108880

SN - 1535-6108

VL - 13

SP - 355

EP - 364

JO - Cancer cell

JF - Cancer cell

IS - 4

ER -

Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma Development

Abstract

Keywords

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