ELK4 neutralization sensitizes glioblastoma to apoptosis through downregulation of the anti-apoptotic protein Mcl-1

Day, Bryan W., Stringer, Brett W., Spanevello, Mark D., Charmsaz, Sara, Jamieson, Paul R., Ensbey, Kathleen S., Carter, Jacinta C., Cox, Joanne M., Ellis, Vicky J., Brown, Christopher L., Walker, David G., Inglis, Po L., Allan, Suzanne, Reynolds, Brent A., Lickliter, Jason D. and Boyd, Andrew W. (2011) ELK4 neutralization sensitizes glioblastoma to apoptosis through downregulation of the anti-apoptotic protein Mcl-1. Neuro-Oncology, 13 11: 1202-1212. doi:10.1093/neuonc/nor119

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Author Day, Bryan W.
Stringer, Brett W.
Spanevello, Mark D.
Charmsaz, Sara
Jamieson, Paul R.
Ensbey, Kathleen S.
Carter, Jacinta C.
Cox, Joanne M.
Ellis, Vicky J.
Brown, Christopher L.
Walker, David G.
Inglis, Po L.
Allan, Suzanne
Reynolds, Brent A.
Lickliter, Jason D.
Boyd, Andrew W.
Title ELK4 neutralization sensitizes glioblastoma to apoptosis through downregulation of the anti-apoptotic protein Mcl-1
Journal name Neuro-Oncology   Check publisher's open access policy
ISSN 1522-8517
Publication date 2011-11
Sub-type Article (original research)
DOI 10.1093/neuonc/nor119
Volume 13
Issue 11
Start page 1202
End page 1212
Total pages 11
Place of publication Cary, NC, United States
Publisher Oxford University Press
Collection year 2012
Language eng
Abstract Glioma is the most common adult primary brain tumor. Its most malignant form, glioblastoma multiforme (GBM), is almost invariably fatal, due in part to the intrinsic resistance of GBM to radiation- and chemotherapy-induced apoptosis. We analyzed B-cell leukemia–2 (Bcl-2) anti-apoptotic proteins in GBM and found myeloid cell leukemia–1 (Mcl-1) to be the highest expressed in the majority of malignant gliomas. Mcl-1 was functionally important, as neutralization of Mcl-1 induced apoptosis and increased chemotherapy-induced apoptosis. To determine how Mcl-1 was regulated in glioma, we analyzed the promoter and identified a novel functional single nucleotide polymorphism in an uncharacterized E26 transformation-specific (ETS) binding site. We identified the ETS transcription factor ELK4 as a critical regulator of Mcl-1 in glioma, since ELK4 downregulation was shown to reduce Mcl-1 and increase sensitivity to apoptosis. Importantly the presence of the single nucleotide polymorphism, which ablated ELK4 binding in gliomas, was associated with lower Mcl-1 levels and a greater dependence on Bcl-xL. Furthermore, in vivo, ELK4 downregulation reduced tumor formation in glioblastoma xenograft models. The critical role of ELK4 in Mcl-1 expression and protection from apoptosis in glioma defines ELK4 as a novel potential therapeutic target for GBM.
Keyword Apoptosis
ELK4
Glioblastoma
Glioma
Mcl-1
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2012 Collection
School of Medicine Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 10 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 30 Nov 2011, 13:48:09 EST by Matthew Lamb on behalf of School of Medicine