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

Autor: Liko D; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Mitchell L; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Campbell KJ; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Ridgway RA; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Jones C; MRC Toxicology Unit, Hodgkin Building Lancaster Road, Leicester, LE1 9HN, UK., Dudek K; MRC Toxicology Unit, Hodgkin Building Lancaster Road, Leicester, LE1 9HN, UK., King A; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Bryson S; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Stevenson D; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Blyth K; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK., Strathdee D; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Morton JP; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK., Bird TG; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Knight JRP; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK. j.knight@beatson.gla.ac.uk., Willis AE; MRC Toxicology Unit, Hodgkin Building Lancaster Road, Leicester, LE1 9HN, UK., Sansom OJ; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK. o.sansom@beatson.gla.ac.uk.; Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK. o.sansom@beatson.gla.ac.uk.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2019 Dec; Vol. 26 (12), pp. 2535-2550. Date of Electronic Publication: 2019 Mar 11.
DOI: 10.1038/s41418-019-0316-7
Abstrakt: 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.
Databáze: MEDLINE
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