Brf1 loss and not overexpression disrupts tissues homeostasis in the intestine, liver and pancreas

Dritan Liko, Louise Mitchell, Kirsteen J. Campbell, Rachel A. Ridgway, Carolyn Jones, Kate Dudek, Ayala King, Sheila Bryson, David Stevenson, Karen Blyth, Douglas Strathdee, Jennifer P. Morton, Thomas G. Bird, John R. P. Knight, Anne E. Willis, Owen J. Sansom

Research output: Contribution to journalArticlepeer-review

Abstract

RNA polymerase III (Pol-III) transcribes tRNAs and other small RNAs essential for protein synthesis and cell growth. Pol-III is deregulated during carcinogenesis; however, its role in vivo has not been studied. To address this issue, we
manipulated levels of Brf1, a Pol-III transcription factor that is essential for recruitment of Pol-III holoenzyme at tRNA genes in vivo. Knockout of Brf1 led to embryonic lethality at blastocyst stage. In contrast, heterozygous Brf1 mice were
viable, fertile and of a normal size. Conditional deletion of Brf1 in gastrointestinal epithelial tissues, intestine, liver and pancreas, was incompatible with organ homeostasis. Deletion of Brf1 in adult intestine and liver induced apoptosis.
However, Brf1 heterozygosity neither had gross effects in these epithelia nor did it modify tumorigenesis in the intestine or pancreas. Overexpression of BRF1 rescued the phenotypes of Brf1 deletion in intestine and liver but was unable to
initiate tumorigenesis. Thus, Brf1 and Pol-III activity are absolutely essential for normal homeostasis during development and in adult epithelia. However, Brf1 overexpression or heterozygosity are unable to modify tumorigenesis, suggesting a permissive, but not driving role for Brf1 in the development of epithelial cancers of the pancreas and gut.
Original languageEnglish
JournalCell Death and Differentiation
DOIs
Publication statusPublished - 11 Mar 2019

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