Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors

We previously identified 28 cofactors through which a RAS oncoprotein directs transcriptional silencing of Fas and other tumor suppressor genes (TSGs). Here we performed RNAi-based epistasis experiments and found that RAS-directed silencing occurs through a highly ordered pathway that is initiated b...

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Bibliographic Details
Published in:Genes & development 2013-10, Vol.27 (20), p.2221-2226
Main Authors: Wajapeyee, Narendra, Malonia, Sunil K, Palakurthy, Rajendra K, Green, Michael R
Format: Article
Language:English
Subjects:
Animals
DNA Methylation
Epigenesis, Genetic
fas Receptor - genetics
fas Receptor - metabolism
Gene Expression Regulation, Neoplastic
Gene Silencing
Genes, Tumor Suppressor
Mice
Models, Biological
NIH 3T3 Cells
Protein Binding
ras Proteins - genetics
ras Proteins - metabolism
Research Communication
RNA Interference
Signal Transduction
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Summary:We previously identified 28 cofactors through which a RAS oncoprotein directs transcriptional silencing of Fas and other tumor suppressor genes (TSGs). Here we performed RNAi-based epistasis experiments and found that RAS-directed silencing occurs through a highly ordered pathway that is initiated by binding of ZFP354B, a sequence-specific DNA-binding protein, and culminates in recruitment of the DNA methyltransferase DNMT1. RNAi and pharmacological inhibition experiments reveal that silencing requires continuous function of RAS and its cofactors and can be rapidly reversed, which may have therapeutic implications for reactivation of silenced TSGs in RAS-positive cancers.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.227413.113