scholarly journals An aminoacylation independent activity of PheRS/FARS promotes growth and proliferation

2020 ◽  
Author(s):  
Manh Tin Ho ◽  
Jiongming Lu ◽  
Beat Suter
Keyword(s):  
Cell Growth ◽  
Trna Synthetase ◽  
Tumor Formation ◽  
Follicle Cells ◽  
Strong Increase ◽  
Trna Synthetases ◽  
Elevated Expression ◽  
Wing Discs ◽  
Cell Growth And Proliferation ◽  
Normal Twin

Summary / AbstractAminoacyl-tRNA synthetases (aaRSs) not only load the appropriate amino acid onto their cognate tRNA, but many of them perform additional functions that are not necessarily related to their canonical activities. Phenylalanyl-tRNA synthetase (PheRS/FARS) levels are elevated in various cancer cells compared to their normal cell counterparts. However, whether and how these levels might contribute to tumor formation was not clear. Here, we show that PheRS is required for cell growth and proliferation. Interestingly, elevated expression of the α-PheRS subunit alone stimulates cell growth and proliferation. In the wing discs system, this leads to a strong increase of mitotic cells. Clonal analysis of twin spots in dividing follicle cells revealed that elevated expression of the α-PheRS subunit causes cells to grow and proliferate about 25% faster than their normal twin cells. Importantly, this stimulation of growth and proliferation neither required the β-PheRS subunit nor the aminoacylation activity, and it did not visibly stimulate translation. These results, therefore, revealed a non-canonical function of an ancient housekeeping enzyme, providing novel insight into its roles in health and diseases.

scholarly journals A translation-independent function of PheRS activates growth and proliferation in Drosophila

2021 ◽  
Vol 14 (3) ◽  
pp. dmm048132 ◽  
Author(s):  
Manh Tin Ho ◽  
Jiongming Lu ◽  
Dominique Brunßen ◽  
Beat Suter
Keyword(s):  
Trna Synthetase ◽  
Wing Disc ◽  
Follicle Cells ◽  
Independent Function ◽  
Proliferating Cells ◽  
Trna Synthetases ◽  
Elevated Expression ◽  
Aminoacyl Transfer ◽  
Cell Growth And Proliferation ◽  
Normal Twin

ABSTRACTAminoacyl transfer RNA (tRNA) synthetases (aaRSs) not only load the appropriate amino acid onto their cognate tRNAs, but many of them also perform additional functions that are not necessarily related to their canonical activities. Phenylalanyl tRNA synthetase (PheRS/FARS) levels are elevated in multiple cancers compared to their normal cell counterparts. Our results show that downregulation of PheRS, or only its α-PheRS subunit, reduces organ size, whereas elevated expression of the α-PheRS subunit stimulates cell growth and proliferation. In the wing disc system, this can lead to a 67% increase in cells that stain for a mitotic marker. Clonal analysis of twin spots in the follicle cells of the ovary revealed that elevated expression of the α-PheRS subunit causes cells to grow and proliferate ∼25% faster than their normal twin cells. This faster growth and proliferation did not affect the size distribution of the proliferating cells. Importantly, this stimulation proliferation turned out to be independent of the β-PheRS subunit and the aminoacylation activity, and it did not visibly stimulate translation.This article has an associated First Person interview with the joint first authors of the paper.

scholarly journals Control of Cell Growth and Proliferation by the Tribbles Pseudokinase: Lessons from Drosophila

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 883
Author(s):  
Leonard L. Dobens ◽  
Christopher Nauman ◽  
Zachary Fischer ◽  
Xiaolan Yao
Keyword(s):  
Cell Growth ◽  
Tumor Formation ◽  
Hippo Signaling ◽  
Lung Cancers ◽  
Stem Cell Quiescence ◽  
Enhancer Binding Protein ◽  
Drosophila Model ◽  
Proliferation And Differentiation ◽  
Regulate Cell Growth ◽  
Cell Growth And Proliferation

The Tribbles (Trib) family of pseudokinase proteins regulate cell growth, proliferation, and differentiation during normal development and in response to environmental stress. Mutations in human Trib isoforms (Trib1, 2, and 3) have been associated with metabolic disease and linked to leukemia and the formation of solid tumors, including melanomas, hepatomas, and lung cancers. Drosophila Tribbles (Trbl) was the first identified member of this sub-family of pseudokinases and shares a conserved structure and similar functions to bind and direct the degradation of key mediators of cell growth and proliferation. Common Trib targets include Akt kinase (also known as protein kinase B), C/EBP (CAAT/enhancer binding protein) transcription factors, and Cdc25 phosphatases, leading to the notion that Trib family members stand athwart multiple pathways modulating their growth-promoting activities. Recent work using the Drosophila model has provided important insights into novel facets of conserved Tribbles functions in stem cell quiescence, tissue regeneration, metabolism connected to insulin signaling, and tumor formation linked to the Hippo signaling pathway. Here we highlight some of these recent studies and discuss their implications for understanding the complex roles Tribs play in cancers and disease pathologies.

scholarly journals Selective Inhibitors of Methionyl-tRNA Synthetase Have Potent Activity against Trypanosoma brucei Infection in Mice

2011 ◽  
Vol 55 (5) ◽  
pp. 1982-1989 ◽  
Author(s):  
Sayaka Shibata ◽  
J. Robert Gillespie ◽  
Angela M. Kelley ◽  
Alberto J. Napuli ◽  
Zhongsheng Zhang ◽  
...  
Keyword(s):  
Cell Growth ◽  
Trypanosoma Brucei ◽  
Drug Targets ◽  
Treatment Options ◽  
Therapeutic Index ◽  
Comparative Sequence Analysis ◽  
Trna Synthetase ◽  
Sub Saharan Africa ◽  
Content Type ◽  
Trna Synthetases

ABSTRACTHuman African trypanosomiasis continues to be an important public health threat in extensive regions of sub-Saharan Africa. Treatment options for infected patients are unsatisfactory due to toxicity, difficult administration regimes, and poor efficacy of available drugs. The aminoacyl-tRNA synthetases were selected as attractive drug targets due to their essential roles in protein synthesis and cell survival. Comparative sequence analysis disclosed differences between the trypanosome and mammalian methionyl-tRNA synthetases (MetRSs) that suggested opportunities for selective inhibition using drug-like molecules. Experiments using RNA interference on the single MetRS ofTrypanosoma bruceidemonstrated that this gene product was essential for normal cell growth. Small molecules (diaryl diamines) similar to those shown to have potent activity on prokaryotic MetRS enzymes were synthesized and observed to have inhibitory activity on theT. bruceiMetRS (50% inhibitory concentration, <50 nM) and on bloodstream forms ofT. bruceicultures (50% effective concentration, as low as 4 nM). Twenty-one compounds had a close correlation between enzyme binding/inhibition andT. bruceigrowth inhibition, indicating that they were likely to be acting on the intended target. The compounds had minimal effects on mammalian cell growth at 20 μM, demonstrating a wide therapeutic index. The most potent compound was tested in the murine model of trypanosomiasis and demonstrated profound parasite suppression and delayed mortality. A homology model of theT. bruceiMetRS based on other MetRS structures was used to model binding of the lead diaryl diamine compounds. Future studies will focus on improving the pharmacological properties of the MetRS inhibitors.

Glutamyl and Glutaminyl-tRNA Synthetases Are a Promising Target for the Design of Threonine-Producing Strain

2019 ◽  
Vol 35 (6) ◽  
pp. 39-50
Author(s):  
T.V. Yuzbashev ◽  
A.S. Fedorov ◽  
F.V. Bondarenko ◽  
A.S. Savchenko ◽  
T.V. Vybornaya ◽  
...  
Keyword(s):  
Biomass Accumulation ◽  
Trna Synthetase ◽  
Temperature Sensitive ◽  
Original Strain ◽  
Trna Synthetases ◽  
Resource Center ◽  
Promising Target ◽  
The Russian Federation ◽  
Increase In Productivity ◽  
Culture Growth

The present work describes an approach that improves the properties of the strain producing L-threonine via the reduction in the biomass accumulation during fermentation. Glutamyl- and glutaminyl-tRNA synthetases were chosen as targets. Mutants carrying temperature-sensitive alleles were obtained. It was shown that the used system caused the suppression of the function of tRNA synthetases which led to a rapid arrest of the culture growth, and an increase in productivity and yield of the L-threonine synthesis. One of the temperature-sensitive strains was used to obtain under non-permissive conditions of mutants with the suppressed above phenotype. Some of these mutants accumulate less biomass and produce by 10-12% more threonine than the original strain. Escherichia coli, producing strain, threonine, aminoacyl-tRNA synthetase, ts-mutation This work was supported by the Ministry of Science and Higher Education of the Russian Federation (project code RFMEFI61017X0011), and it was carried out using the equipment of the National Bio-Resource Center All-Russian Collection of Industrial Microorganisms, NRC «Kurchatov Institute» - GosNIIgenetika.

scholarly journals Zinc-dependent cell growth conferred by mutant tRNA synthetase.

1994 ◽  
Vol 269 (32) ◽  
pp. 20217-20220
Author(s):  
J.A. Landro ◽  
P. Schimmel
Keyword(s):  
Cell Growth ◽  
Trna Synthetase ◽  
Dependent Cell

scholarly journals HOXB4 inhibits the proliferation and tumorigenesis of cervical cancer cells by downregulating the activity of Wnt/β-catenin signaling pathway

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dan Lei ◽  
Wen-Ting Yang ◽  
Peng-Sheng Zheng
Keyword(s):  
Cervical Cancer ◽  
Cell Growth ◽  
Signaling Pathway ◽  
Cancer Cell ◽  
Tumor Formation ◽  
Cervical Cancer Cell ◽  
Cancer Cell Growth ◽  
Bioinformatics Analyses

AbstractHomeobox B4 (HOXB4), which belongs to the homeobox (HOX) family, possesses transcription factor activity and has a crucial role in stem cell self-renewal and tumorigenesis. However, its biological function and exact mechanism in cervical cancer remain unknown. Here, we found that HOXB4 was markedly downregulated in cervical cancer. We demonstrated that HOXB4 obviously suppressed cervical cancer cell proliferation and tumorigenic potential in nude mice. Additionally, HOXB4-induced cell cycle arrest at the transition from the G0/G1 phase to the S phase. Conversely, loss of HOXB4 promoted cervical cancer cell growth both in vitro and in vivo. Bioinformatics analyses and mechanistic studies revealed that HOXB4 inhibited the activity of the Wnt/β-catenin signaling pathway by direct transcriptional repression of β-catenin. Furthermore, β-catenin re-expression rescued HOXB4-induced cervical cancer cell defects. Taken together, these findings suggested that HOXB4 directly transcriptional repressed β-catenin and subsequently inactivated the Wnt/β-catenin signaling pathway, leading to significant inhibition of cervical cancer cell growth and tumor formation.

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