Modulated Expression of Specific tRNAs Drives Gene Expression and Cancer Progression

Goodarzi, Hani; Nguyen, Hoang Cong; Zhang, Steven; Dill, Brian D.; Molina, Henrik; Tavazoie, Sohail F.

doi:10.1016/j.cell.2016.05.046

Cited by 393 publications

(408 citation statements)

References 37 publications

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“…2 Other research groups have also reported dramatic and significant effects of single tRNA transfection, 4 , 6 , 7 and we confirmed the same results in stable NIH3T3 MEF cells, where a single copy of tRNA Leu CAG was inserted in the genomic region (Fig. 6A-C and Fig.…”

Section: Discussionsupporting

confidence: 89%

“…17 A recent study had revealed that breast cancer metastasis was promoted by tRNA Glu UUC and tRNA Arg CCG . 4 This study demonstrated that overexpression of specific tRNAs could modulate protein expression in a codon-dependent manner, resulting in metastatic behavior. It also shed light on the importance of quantitative changes in tRNAs.…”

Section: Introductionmentioning

confidence: 84%

“…49 These new roles of tRNAs have been observed in prokaryotes as well as eukaryotes, and they are involved in various cellular phenomena, including haeme and chlorophyll biosynthesis, antibiotic cellular permeability, energy metabolism, amino acid biosynthesis and protein degradation, reverse transcription of viruses, cell apoptosis and survival, and cancer progression. 4-6 , 10 , 37 , 50-55 In this study, we investigated the novel functions of tRNAs, especially tRNA Leu , which promoted cell proliferation via RSK/MSK signaling.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, sequence similarities do not guarantee the equal function or expression of tRNAs. 3 , 4 …”

Section: Introductionmentioning

confidence: 99%

“…4 , 14 , 15 Given that tRNA abundance is correlated with protein synthesis, 16 it has been hypothesized that tRNA content may affect the rate of translation, globally or for a subset of proteins based on codon usage. 17 A recent study had revealed that breast cancer metastasis was promoted by tRNA Glu UUC and tRNA Arg CCG .…”

Section: Introductionmentioning

confidence: 99%

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Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

et al. 2018

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While transfer-RNAs (tRNAs) are known to transport amino acids to ribosome, new functions are being unveiled from tRNAs and their fragments beyond protein synthesis. Here we show that phosphorylation of 90-kDa RPS6K (ribosomal proteins S6 kinase) was enhanced by tRNALeu overexpression under amino acids starvation condition. The phosphorylation of 90-kDa RPS6K was decreased by siRNA specific to tRNALeu and was independent to mTOR (mammalian target of rapamycin) signaling. Among the 90-kDa RPS6K family, RSK1 (ribosomal S6 kinase 1) and MSK2 (mitogen-and stress-activated protein kinase 2) were the major kinases phosphorylated by tRNALeu overexpression. Through SILAC (stable isotope labeling by/with amino acids in cell culture) and combined mass spectrometry analysis, we identified EBP1 (ErbB3-binding protein 1) as the tRNALeu-binding protein. We suspected that the overexpression of free tRNALeu would reinforce ErbB2/ErbB3 signaling pathway by disturbing the interaction between ErbB3 and EBP1, resulting in RSK1/MSK2 phosphorylation, improving cell proliferation and resistance to death. Analysis of samples from patients with breast cancer also indicated an association between tRNALeu overexpression and the ErbB2-positive population. Our results suggested a possible link between tRNALeu overexpression and RSK1/MSK2 activation and ErbB2/ErbB3 signaling.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

“…In addition, sequence similarities do not guarantee the equal function or expression of tRNAs. 3 , 4 …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

et al. 2018

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A simplified qPCR method revealing tRNAome remodeling upon infection by genotype 3 hepatitis E virus

Zhang

et al. 2020

FEBS Letters

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The landscape of tRNA-viral codons regulates viral adaption at the translational level, presumably through adapting to host codon usage or modulating the host tRNAome. We found that the major zoonotic genotype of hepatitis E virus (HEV) has not adapted to host codon usage, prompting exploration of the effects of HEV infection on the host tRNAome. However, tRNAome quantification is largely impeded by the extremely short sequences of tRNAs and redundancy of tRNA genes. Here, we present a length-extension and stepwise simplified qPCR method that utilizes a universal DNA/RNA hybrid tRNA adaptor and degenerate primers. Using this novel methodology, we observe that HEV infection dramatically reprograms the hepatic tRNAome, which is likely to facilitate translation of viral RNAs. This tRNAome quantification method bears broad implications for future tRNA research and possibly tRNA-based diagnostics.

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Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Zeng

Shi

et al. 2017

Molecular Oncology

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TFIIB‐related factor 1 (Brf1) modulates the transcription of RNA Pol III genes (polymerase‐dependent genes). Upregulation of Pol III genes enhances tRNA and 5S RNA production and increases the translational capacity of cells to promote cell transformation and tumor development. However, the significance of Brf1 overexpression in human breast cancer (HBC) remains to be investigated. Here, we investigate whether Brf1 expression is increased in the samples of HBC, and we explore its molecular mechanism and the significance of Brf1 expression in HBC. Two hundred and eighteen samples of HBC were collected to determine Brf1 expression by cytological and molecular biological approaches. We utilized colocalization, coimmunoprecipitation, and chromatin immunoprecipitation methods to explore the interaction of Brf1 with estrogen receptor alpha (ERα). We determined how Brf1 and ERα modulate Pol III genes. The results indicated that Brf1 is overexpressed in most cases of HBC, which is associated with an ER‐positive status. The survival period of the cases with high Brf1 expression is significantly longer than those with low levels of Brf1 after hormone treatment. ERα mediates Brf1 expression. Brf1 and ERα are colocalized in the nucleus. These results indicate an interaction between Brf1 and ERα, which synergistically regulates the transcription of Pol III genes. Inhibition of ERα by its siRNA or tamoxifen reduces cellular levels of Brf1 and Pol III gene expression and decreases the rate of colony formation of breast cancer cells. Together, these studies demonstrate that Brf1 is a good biomarker for the diagnosis and prognosis of HBC. This interaction of Brf1 with ERα and Brf1 itself are potential therapeutic targets for this disease.

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Modulated Expression of Specific tRNAs Drives Gene Expression and Cancer Progression

Cited by 393 publications

References 37 publications

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

A simplified qPCR method revealing tRNAome remodeling upon infection by genotype 3 hepatitis E virus

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

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