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

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

doi:10.1038/s41418-019-0316-7

Cited by 11 publications

(7 citation statements)

References 77 publications

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“…An in vivo model with prostate epithelium-specific overexpression of BRF1 was generated by inter-crossing BRF1 mice [18] with the Pbsn (PB)-Cre4 strain [19] to generate PB-Cre4:BRF1 (herein referred to as BRF1 Tg ) mice (see Supplementary methods; Fig. 2a).…”

Section: Increased Brf1 Accelerates Prostate Tumourigenesis In Vivomentioning

confidence: 99%

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration

et al. 2019

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BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and is elevated in numerous cancers. Here, we report that elevated levels of BRF1 associate with poor prognosis in human prostate cancer. In vitro studies in human prostate cancer cell lines demonstrated that transient overexpression of BRF1 increased cell proliferation whereas the transient downregulation of BRF1 reduced proliferation and mediated cell cycle arrest. Consistent with our clinical observations, BRF1 overexpression in a Pten-deficient mouse (Pten Δ/Δ BRF1 Tg) prostate cancer model accelerated prostate carcinogenesis and shortened survival. In Pten Δ/Δ BRF1 Tg tumours, immune and inflammatory processes were altered, with reduced tumoral infiltration of neutrophils and CD4 positive T cells, which can be explained by decreased levels of complement factor D (CFD) and C7 components of the complement cascade, an innate immune pathway that influences the adaptive immune response. We tested if the secretome was involved in BRF1-driven tumorigenesis. Unbiased proteomic analysis on BRF1-overexpresing PC3 cells confirmed reduced levels of CFD in the secretome, implicating the complement system in prostate carcinogenesis. We further identify that expression of C7 significantly correlates with expression of CD4 and has the potential to alter clinical outcome in human prostate cancer, where low levels of C7 associate with poorer prognosis.

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Section: Increased Brf1 Accelerates Prostate Tumourigenesis In Vivomentioning

confidence: 99%

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration

et al. 2019

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“…Further, inactivation of the genes for the RPI factors Ubtf (ubtf) and Rrn3/TIF1A (rrn3) arrest mouse development during early cleavage stages (24,26). A similar argument could be made for inactivation of RPIII/PolIII transcription since loss of the Brf1 subunit of the TFIIIB complex also causes developmental arrest during early cleavage stages (49). We conclude that the maternal protein translation machinery is limiting in the cleavage embryo and must be replenished by zygotic expression to allow further development.…”

Section: Supporting Information Captions Supporting Resultsmentioning

confidence: 68%

Bidirectional cooperation between Ubtf1 and SL1 determines RNA Polymerase I promoter recognition in cell and is negatively affected in the UBTF-E210K neuroregression syndrome

Tremblay¹,

Sibai

Valere

et al. 2021

Preprint

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Transcription of the ~200 mouse and human ribosomal RNA genes (rDNA) by RNA Polymerase I (RPI/PolR1) accounts for 80% of total cellular RNA, around 35% of all nuclear RNA synthesis, and determines the cytoplasmic ribosome complement. It is therefore a major factor controlling cell growth and its misfunction has been implicated in hypertrophic and developmental disorders. Activation of each rDNA repeat requires nucleosome replacement by the architectural multi-HMGbox factor UBTF to create a 15kbp nucleosome free region (NFR). Formation of this NFR is also essential for recruitment of the TBP-TAF I factor SL1 and for preinitiation complex (PIC) formation at the gene and enhancer-associated promoters of the rDNA. However, these promoters show little sequence commonality and neither UBTF nor SL1 display significant DNA sequence binding specificity, making what drives PIC formation a mystery. Here we show that cooperation between SL1 and the longer UBTF1 splice variant generates the specificity required for rDNA promoter recognition in cell . We find that conditional deletion of the Taf1b subunit of SL1 causes a striking depletion UBTF at both rDNA promoters but not elsewhere across the rDNA. We also find that while both UBTF1 and -2 variants bind throughout the rDNA NFR, only UBTF1 is present with SL1 at the promoters. The data strongly suggest an induced-fit model of RPI promoter recognition in which UBTF1 plays an architectural role. Interestingly, a recurrent UBTF-E210K mutation and the cause of a pediatric neurodegeneration syndrome provides indirect support for this model. E210K knock-in cells show enhanced levels of the UBTF1 splice variant and a concomitant increase in active rDNA copies. In contrast, they also display reduced rDNA transcription and promoter recruitment of SL1. We suggest the underlying cause of the UBTF-E210K syndrome is therefore a reduction in cooperative UBTF1-SL1 promoter recruitment that may be partially compensated by enhanced rDNA activation.

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“…Further analysis indicates that mutant MSK1 in either These studies demonstrate that MSK1 indeed mediates the activities of Brf1 and Pol III genes. Brf1 is a key factor which involves organ development [40]. Although our early studies have indicated that alcohol increases expression of Brf1 and Pol III genes of hepatocytes [7,33], it remains to be elucidated how alcohol affects Brf1 Oxidative Medicine and Cellular Longevity transcription.…”

Section: Discussionmentioning

confidence: 99%

“…Brf1 is a key factor which involves organ development [ 40 ]. Although our early studies have indicated that alcohol increases expression of Brf1 and Pol III genes of hepatocytes [ 7 , 33 ], it remains to be elucidated how alcohol affects Brf1 transcription.…”

Section: Discussionmentioning

confidence: 99%

Mitogen- and Stress-Activated Protein Kinase 1 Mediates Alcohol-Upregulated Transcription of Brf1 and tRNA Genes to Cause Phenotypic Alteration

Lin

Huang

Ren

et al. 2020

Oxidative Medicine and Cellular Longevity

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Upregulation of Brf1 (TFIIB-related factor 1) and Pol III gene (RNA polymerase III-dependent gene, such as tRNAs and 5S rRNA) activities is associated with cell transformation and tumor development. Alcohol intake causes liver injury, such as steatosis, inflammation, fibrosis, and cirrhosis, which enhances the risk of HCC development. However, the mechanism of alcohol-promoted HCC remains to be explored. We have designed the complementary research system, which is composed of cell lines, an animal model, human samples, and experiments in vivo and in vitro, to carry out this project by using molecular biological, biochemical, and cellular biological approaches. It is a unique system to explore the mechanism of alcohol-associated HCC. Our results indicate that alcohol upregulates Brf1 and Pol III gene (tRNAs and 5S rRNA) transcription in primary mouse hepatocytes, immortalized mouse hepatocyte-AML-12 cells, and engineered human HepG2-ADH cells. Alcohol activates MSK1 to upregulate expression of Brf1 and Pol III genes, while inhibiting MSK1 reduces transcription of Brf1 and Pol III genes in alcohol-treated cells. The inhibitor of MSK1, SB-747651A, decreases the rates of cell proliferation and colony formation. Alcohol feeding promotes liver tumor development of the mouse. These results, for the first time, show the identification of the alcohol-response promoter fragment of the Pol III gene key transcription factor, Brf1. Our studies demonstrate that Brf1 expression is elevated in HCC tumor tissues of mice and humans. Alcohol increases cellular levels of Brf1, resulting in enhancement of Pol III gene transcription in hepatocytes through MSK1. Our mechanism analysis has demonstrated that alcohol-caused high-response fragment of the Brf1 promoter is at p-382/+109bp. The MSK1 inhibitor SB-747651A is an effective reagent to repress alcohol-induced cell proliferation and colony formation, which is a potential pharmaceutical agent. Developing this inhibitor as a therapeutic approach will benefit alcohol-associated HCC patients.

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

Cited by 11 publications

References 77 publications

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration

Bidirectional cooperation between Ubtf1 and SL1 determines RNA Polymerase I promoter recognition in cell and is negatively affected in the UBTF-E210K neuroregression syndrome

Mitogen- and Stress-Activated Protein Kinase 1 Mediates Alcohol-Upregulated Transcription of Brf1 and tRNA Genes to Cause Phenotypic Alteration

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