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

Autor: Owen J. Sansom, Carolyn J.P. Jones, John R. P. Knight, Kirsteen J. Campbell, Rachel A. Ridgway, Sheila Bryson, Karen Blyth, Thomas G. Bird, Kate Dudek, Ayala King, Douglas Strathdee, Dritan Liko, David A. Stevenson, Anne E. Willis, Louise Mitchell, Jennifer P. Morton
Rok vydání: 2019
Předmět:
Zdroj: Liko, D, Mitchell, L, Campbell, K J, Ridgway, R A, Jones, C, Dudek, K, King, A, Bryson, S, Stevenson, D, Blyth, K, Strathdee, D, Morton, J P, Bird, T G, Knight, J R P, Willis, A E & Sansom, O J 2019, ' Brf1 loss and not overexpression disrupts tissues homeostasis in the intestine, liver and pancreas ', Cell Death and Differentiation . https://doi.org/10.1038/s41418-019-0316-7
Cell death and differentiation
Liko, D, Mitchell, L, Campbell, K J, Ridgway, R A, Jones, C, Dudek, K, King, A, Bryson, S, Stevenson, D A, Blyth, K, Strathdee, D, Morton, J P, Bird, T G, Knight, J R P, Willis, A E & Sansom, O J 2019, ' Brf1 loss and not overexpression disrupts tissues homeostasis in the intestine, liver and pancreas ', Cell Death and Differentiation, vol. 26, no. 12, pp. 2535-2550 . https://doi.org/10.1038/s41418-019-0316-7
ISSN: 1476-5403
1350-9047
DOI: 10.1038/s41418-019-0316-7
Popis: 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, wemanipulated 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 wereviable, 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 toinitiate 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: OpenAIRE
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