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Kulic, I.* ; Robertson, G.* ; Chang, L.* ; Baker, J.H.* ; Lockwood, W.W.* ; Mok, W.* ; Fuller, M.* ; Fournier, M.* ; Wong, N.* ; Chou, V.* ; Robinson, M.D.* ; Chun, H.J.* ; Gilks, B.* ; Kempkes, B. ; Thomson, T.A.* ; Hirst, M.* ; Minchinton, A.I.* ; Lam, W.L.* ; Jones, S.* ; Marra, M.* ; Karsan, A.*

Loss of the Notch effector RBPJ promotes tumorigenesis.

J. Exp. Med. 212, 37-52 (2015)
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Aberrant Notch activity is oncogenic in several malignancies, but it is unclear how expression or function of downstream elements in the Notch pathway affects tumor growth. Transcriptional regulation by Notch is dependent on interaction with the DNA-binding transcriptional repressor, RBPJ, and consequent derepression or activation of associated gene promoters. We show here that RBPJ is frequently depleted in human tumors. Depletion of RBPJ in human cancer cell lines xenografted into immunodeficient mice resulted in activation of canonical Notch target genes, and accelerated tumor growth secondary to reduced cell death. Global analysis of activated regions of the genome, as defined by differential acetylation of histone H4 (H4ac), revealed that the cell death pathway was significantly dysregulated in RBPJ-depleted tumors. Analysis of transcription factor binding data identified several transcriptional activators that bind promoters with differential H4ac in RBPJ-depleted cells. Functional studies demonstrated that NF-κB and MYC were essential for survival of RBPJ-depleted cells. Thus, loss of RBPJ derepresses target gene promoters, allowing Notch-independent activation by alternate transcription factors that promote tumorigenesis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Nf-kappa-b; Transcription Factor-binding; To-mesenchymal Transition; Cancer Genomics; Breast-cancer; C-myc; Dna; Activation; Complex; Pathway
Language english
Publication Year 2015
Prepublished in Year 2014
HGF-reported in Year 2014
ISSN (print) / ISBN 0022-1007
e-ISSN 1540-9538
Journal Journal of Experimental Medicine
Quellenangaben Volume: 212, Issue: 1, Pages: 37-52 Article Number: , Supplement: ,
Publisher Rockefeller University Press
Publishing Place New York
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
PSP Element(s) G-501500-002
PubMed ID 25512468
DOI 10.1084/jem.20121192
WOS ID WOS:000347819800007
Scopus ID 84921368162
Erfassungsdatum 2014-12-31
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