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.
journal_name
Neuro Oncoljournal_title
Neuro-oncologyauthors
Day BW,Stringer BW,Spanevello MD,Charmsaz S,Jamieson PR,Ensbey KS,Carter JC,Cox JM,Ellis VJ,Brown CL,Walker DG,Inglis PL,Allan S,Reynolds BA,Lickliter JD,Boyd AWdoi
10.1093/neuonc/nor119subject
Has Abstractpub_date
2011-11-01 00:00:00pages
1202-12issue
11eissn
1522-8517issn
1523-5866pii
nor119journal_volume
13pub_type
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