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Loss of the Notch effector RBPJ promotes tumorigenesis.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2015 Jan 12; Vol. 212 (1), pp. 37-52. Date of Electronic Publication: 2014 Dec 15. - Publication Year :
- 2015
-
Abstract
- 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.<br /> (© 2015 Kulic et al.)
- Subjects :
- Acetylation
Animals
Carcinogenesis metabolism
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
HEK293 Cells
Histones metabolism
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein metabolism
Mice
Mice, Inbred NOD
Mice, SCID
Mutation
NF-kappa B metabolism
Neoplasms metabolism
Neoplasms pathology
Promoter Regions, Genetic genetics
Protein Binding
Proto-Oncogene Proteins c-myc metabolism
RNA Interference
Receptors, Notch metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction genetics
Transplantation, Heterologous
Carcinogenesis genetics
Immunoglobulin J Recombination Signal Sequence-Binding Protein genetics
Neoplasms genetics
Receptors, Notch genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 212
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 25512468
- Full Text :
- https://doi.org/10.1084/jem.20121192