Feedback Circuit Among INK4 Tumor Suppressors Constrains Human Glioblastoma Development

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2008 Apr 9

PMID 18394558

Citations 73

Authors

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

Affiliations

Soon will be listed here.

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.

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References

Blais A, Monte D, Pouliot F, Labrie C . Regulation of the human cyclin-dependent kinase inhibitor p18INK4c by the transcription factors E2F1 and Sp1. J Biol Chem. 2002; 277(35):31679-93. DOI: 10.1074/jbc.M204554200. View

Li P, Nijhawan D, Budihardjo I, Srinivasula S, Ahmad M, Alnemri E . Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997; 91(4):479-89. DOI: 10.1016/s0092-8674(00)80434-1. View

Hunter S, Brat D, Olson J, von Deimling A, Zhou W, Van Meir E . Alterations in molecular pathways of diffusely infiltrating glial neoplasms: application to tumor classification and anti-tumor therapy (Review). Int J Oncol. 2003; 23(4):857-69. View

Furnari F, Fenton T, Bachoo R, Mukasa A, Stommel J, Stegh A . Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 2007; 21(21):2683-710. DOI: 10.1101/gad.1596707. View

Nigro J, Misra A, Zhang L, Smirnov I, Colman H, Griffin C . Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma. Cancer Res. 2005; 65(5):1678-86. DOI: 10.1158/0008-5472.CAN-04-2921. View

Mao J, Perez-Losada J, Wu D, Delrosario R, Tsunematsu R, Nakayama K . Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Nature. 2004; 432(7018):775-9. DOI: 10.1038/nature03155. View

Ramsey M, Krishnamurthy J, Pei X, Torrice C, Lin W, Carrasco D . Expression of p16Ink4a compensates for p18Ink4c loss in cyclin-dependent kinase 4/6-dependent tumors and tissues. Cancer Res. 2007; 67(10):4732-41. DOI: 10.1158/0008-5472.CAN-06-3437. View

Tonon G, Wong K, Maulik G, Brennan C, Feng B, Zhang Y . High-resolution genomic profiles of human lung cancer. Proc Natl Acad Sci U S A. 2005; 102(27):9625-30. PMC: 1160520. DOI: 10.1073/pnas.0504126102. View

Watanabe T, Hirota Y, Arakawa Y, Fujisawa H, Tachibana O, Hasegawa M . Frequent LOH at chromosome 12q22-23 and Apaf-1 inactivation in glioblastoma. Brain Pathol. 2003; 13(4):431-9. PMC: 8095738. DOI: 10.1111/j.1750-3639.2003.tb00474.x. View

10.

Soengas M, Capodieci P, Polsky D, Mora J, Esteller M, McCombie R . Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature. 2001; 409(6817):207-11. DOI: 10.1038/35051606. View

11.

Hagedorn M, Delugin M, Abraldes I, Allain N, Belaud-Rotureau M, Turmo M . FBXW7/hCDC4 controls glioma cell proliferation in vitro and is a prognostic marker for survival in glioblastoma patients. Cell Div. 2007; 2:9. PMC: 1819378. DOI: 10.1186/1747-1028-2-9. View

12.

Venkatraman E, Olshen A . A faster circular binary segmentation algorithm for the analysis of array CGH data. Bioinformatics. 2007; 23(6):657-63. DOI: 10.1093/bioinformatics/btl646. View

13.

Stambolic V, Suzuki A, de la Pompa J, Brothers G, Mirtsos C, Sasaki T . Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998; 95(1):29-39. DOI: 10.1016/s0092-8674(00)81780-8. View

14.

Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G . Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res. 2005; 65(17):7591-5. DOI: 10.1158/0008-5472.CAN-05-1855. View

15.

Mulholland P, Fiegler H, Mazzanti C, Gorman P, Sasieni P, Adams J . Genomic profiling identifies discrete deletions associated with translocations in glioblastoma multiforme. Cell Cycle. 2006; 5(7):783-91. DOI: 10.4161/cc.5.7.2631. View

16.

Liu F, Park P, Lai W, Maher E, Chakravarti A, Durso L . A genome-wide screen reveals functional gene clusters in the cancer genome and identifies EphA2 as a mitogen in glioblastoma. Cancer Res. 2006; 66(22):10815-23. DOI: 10.1158/0008-5472.CAN-06-1408. View

17.

Malyukova A, Dohda T, von der Lehr N, Akhoondi S, Akhondi S, Corcoran M . The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. Cancer Res. 2007; 67(12):5611-6. DOI: 10.1158/0008-5472.CAN-06-4381. View

18.

Hyman E, Kauraniemi P, Hautaniemi S, Wolf M, Mousses S, Rozenblum E . Impact of DNA amplification on gene expression patterns in breast cancer. Cancer Res. 2002; 62(21):6240-5. View

19.

Kotliarov Y, Steed M, Christopher N, Walling J, Su Q, Center A . High-resolution global genomic survey of 178 gliomas reveals novel regions of copy number alteration and allelic imbalances. Cancer Res. 2006; 66(19):9428-36. PMC: 4316202. DOI: 10.1158/0008-5472.CAN-06-1691. View

20.

Huang P, Mukasa A, Bonavia R, Flynn R, Brewer Z, Cavenee W . Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma. Proc Natl Acad Sci U S A. 2007; 104(31):12867-72. PMC: 1937558. DOI: 10.1073/pnas.0705158104. View