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Nehal Thakor
Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Canada

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Note
Published: 01 December 2020 in Biochemistry and Cell Biology
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Glioblastoma multiforme (GBM) is among the deadliest cancers, owing in part to complex inter- and intra-tumor heterogeneity and the presence of a population of stem-like cells called brain tumour stem cells (BTSCs/BTICs). These cancer stem cells survive treatment and confer resistance to the current therapies — namely, radiation and the chemotherapeutic, temozolomide (TMZ). TMZ induces cell death by alkylating DNA, and BTSCs resist this mechanism via a robust DNA damage response. Hence, recent studies aimed to sensitize BTSCs to TMZ using combination therapy, such as inhibition of DNA repair machinery. We have previously demonstrated in established GBM cell lines that eukaryotic initiation factor 5B (eIF5B) promotes the translation of pro-survival and anti-apoptotic proteins. Consequently, silencing eIF5B sensitizes these cells to TRAIL-induced apoptosis. However, established cell lines do not always recapitulate the features of human glioma. Therefore, we investigated this mechanism in patient-derived BTSCs. We show that silencing eIF5B leads to increased TMZ sensitivity in two BTSC lines: BT25 and BT48. Depletion of eIF5B decreases the levels of anti-apoptotic proteins in BT48 and sensitizes these cells to TMZ-induced activation of caspase-3, cleavage of PARP, and apoptosis. We suggest that eIF5B represents a rational target to sensitize GBM tumors to the current standard-of-care.

ACS Style

Joseph A. Ross; Bo Young Ahn; Jennifer King; Kamiko R. Bressler; Donna L. Senger; Nehal Thakor. Eukaryotic initiation factor 5B (eIF5B) regulates temozolomide-mediated apoptosis in brain tumour stem cells (BTSCs). Biochemistry and Cell Biology 2020, 98, 647 -652.

AMA Style

Joseph A. Ross, Bo Young Ahn, Jennifer King, Kamiko R. Bressler, Donna L. Senger, Nehal Thakor. Eukaryotic initiation factor 5B (eIF5B) regulates temozolomide-mediated apoptosis in brain tumour stem cells (BTSCs). Biochemistry and Cell Biology. 2020; 98 (6):647-652.

Chicago/Turabian Style

Joseph A. Ross; Bo Young Ahn; Jennifer King; Kamiko R. Bressler; Donna L. Senger; Nehal Thakor. 2020. "Eukaryotic initiation factor 5B (eIF5B) regulates temozolomide-mediated apoptosis in brain tumour stem cells (BTSCs)." Biochemistry and Cell Biology 98, no. 6: 647-652.

Original paper
Published: 29 October 2020 in Cell Stress and Chaperones
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During the integrated stress response (ISR), global translation initiation is attenuated; however, noncanonical mechanisms allow for the continued translation of specific transcripts. Eukaryotic initiation factor 5B (eIF5B) has been shown to play a critical role in canonical translation as well as in noncanonical mechanisms involving internal ribosome entry site (IRES) and upstream open reading frame (uORF) elements. The uORF-mediated translation regulation of activating transcription factor 4 (ATF4) mRNA plays a pivotal role in the cellular ISR. Our recent study confirmed that eIF5B depletion removes uORF2-mediated repression of ATF4 translation, which results in the upregulation of growth arrest and DNA damage-inducible protein 34 (GADD34) transcription. Accordingly, we hypothesized that eIF5B depletion may reprogram the transcriptome profile of the cell. Here, we employed genome-wide transcriptional analysis on eIF5B-depleted cells. Further, we validate the up- and downregulation of several transcripts from our RNA-seq data using RT-qPCR. We identified upregulated pathways including cellular response to endoplasmic reticulum (ER) stress, and mucin-type O-glycan biosynthesis, as well as downregulated pathways of transcriptional misregulation in cancer and T cell receptor signaling. We also confirm that depletion of eIF5B leads to activation of the c-Jun N-terminal kinase (JNK) arm of the mitogen-activated protein kinase (MAPK) pathway. This data suggests that depletion of eIF5B reprograms the cellular transcriptome and influences critical cellular processes such as ER stress and ISR.

ACS Style

Kamiko R. Bressler; Joseph A. Ross; Slava Ilnytskyy; Keiran Vanden Dungen; Katrina Taylor; Kush Patel; Athanasios Zovoilis; Igor Kovalchuk; Nehal Thakor. Depletion of eukaryotic initiation factor 5B (eIF5B) reprograms the cellular transcriptome and leads to activation of endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase (JNK). Cell Stress and Chaperones 2020, 26, 253 -264.

AMA Style

Kamiko R. Bressler, Joseph A. Ross, Slava Ilnytskyy, Keiran Vanden Dungen, Katrina Taylor, Kush Patel, Athanasios Zovoilis, Igor Kovalchuk, Nehal Thakor. Depletion of eukaryotic initiation factor 5B (eIF5B) reprograms the cellular transcriptome and leads to activation of endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase (JNK). Cell Stress and Chaperones. 2020; 26 (1):253-264.

Chicago/Turabian Style

Kamiko R. Bressler; Joseph A. Ross; Slava Ilnytskyy; Keiran Vanden Dungen; Katrina Taylor; Kush Patel; Athanasios Zovoilis; Igor Kovalchuk; Nehal Thakor. 2020. "Depletion of eukaryotic initiation factor 5B (eIF5B) reprograms the cellular transcriptome and leads to activation of endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase (JNK)." Cell Stress and Chaperones 26, no. 1: 253-264.

Review
Published: 31 October 2019 in Toxins
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Trichothecenes are sesquiterpenoid mycotoxins produced by fungi from the order Hypocreales, including members of the Fusarium genus that infect cereal grain crops. Different trichothecene-producing Fusarium species and strains have different trichothecene chemotypes belonging to the Type A and B class. These fungi cause a disease of small grain cereals, called Fusarium head blight, and their toxins contaminate host tissues. As potent inhibitors of eukaryotic protein synthesis, trichothecenes pose a health risk to human and animal consumers of infected cereal grains. In 2009, Foroud and Eudes published a review of trichothecenes in cereal grains for human consumption. As an update to this review, the work herein provides a comprehensive and multi-disciplinary review of the Fusarium trichothecenes covering topics in chemistry and biochemistry, pathogen biology, trichothecene toxicity, molecular mechanisms of resistance or detoxification, genetics of resistance and breeding strategies to reduce their contamination of wheat and barley.

ACS Style

Nora A. Foroud; Danica Baines; Tatiana Y. Gagkaeva; Nehal Thakor; Ana Badea; Barbara Steiner; Maria Bürstmayr; Hermann Bürstmayr. Trichothecenes in Cereal Grains – An Update. Toxins 2019, 11, 634 .

AMA Style

Nora A. Foroud, Danica Baines, Tatiana Y. Gagkaeva, Nehal Thakor, Ana Badea, Barbara Steiner, Maria Bürstmayr, Hermann Bürstmayr. Trichothecenes in Cereal Grains – An Update. Toxins. 2019; 11 (11):634.

Chicago/Turabian Style

Nora A. Foroud; Danica Baines; Tatiana Y. Gagkaeva; Nehal Thakor; Ana Badea; Barbara Steiner; Maria Bürstmayr; Hermann Bürstmayr. 2019. "Trichothecenes in Cereal Grains – An Update." Toxins 11, no. 11: 634.

Review article
Published: 30 March 2019 in Journal of Applied Microbiology
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Synthetic biology requires the design and implementation of novel enzymes, genetic circuits, or even entire cells, which can be controlled by the user. RNA‐based regulatory elements have many important functional properties in this regard, such as their modular nature and their ability to respond to specific external stimuli. These properties have led to the widespread exploration of their use as gene‐regulation devices in synthetic biology. In this review, we focus on two major types of RNA elements: riboswitches and RNA thermometers (RNATs). We describe their general structure and function, before discussing their potential uses in synthetic biology (e.g. in the production of biofuels and biodegradable plastics). We also discuss their limitations, and novel strategies to implement RNA‐based regulatory devices in biotechnological applications. We close with a description of some common model organisms used in synthetic biology, with a focus on the current applications and limitations of RNA‐based regulation. This article is protected by copyright. All rights reserved.

ACS Style

Jean Claude Nshogozabahizi; Keith L. Aubrey; Joseph A. Ross; Nehal Thakor. Applications and limitations of regulatory RNA elements in synthetic biology and biotechnology. Journal of Applied Microbiology 2019, 127, 968 -984.

AMA Style

Jean Claude Nshogozabahizi, Keith L. Aubrey, Joseph A. Ross, Nehal Thakor. Applications and limitations of regulatory RNA elements in synthetic biology and biotechnology. Journal of Applied Microbiology. 2019; 127 (4):968-984.

Chicago/Turabian Style

Jean Claude Nshogozabahizi; Keith L. Aubrey; Joseph A. Ross; Nehal Thakor. 2019. "Applications and limitations of regulatory RNA elements in synthetic biology and biotechnology." Journal of Applied Microbiology 127, no. 4: 968-984.

Journal article
Published: 22 January 2019 in Cell Death & Disease
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Physiological stress conditions attenuate global mRNA translation via modifications of key eukaryotic initiation factors. However, non-canonical translation initiation mechanisms allow cap-independent translation of certain mRNAs. We have previously demonstrated that eIF5B promotes cap-independent translation of the mRNA encoding the antiapoptotic factor, XIAP, during cellular stress. Here, we show that depletion of eIF5B sensitizes glioblastoma multiforme cells to TRAIL-induced apoptosis by a pathway involving caspases-8, −9, and −7, with no significant effect on cell cycle progression. eIF5B promotes evasion of apoptosis by promoting the translation of several IRES-containing mRNAs, encoding the antiapoptotic proteins XIAP, Bcl-xL, cIAP1, and c-FLIPS. We also show that eIF5B promotes translation of nuclear factor erythroid 2-related factor 2 and suggest that reactive oxygen species contribute to increased apoptosis under conditions of eIF5B depletion. Finally, eIF5B depletion leads to decreased activation of the canonical NF-κB pathway. Taken together, our data suggest that eIF5B represents a regulatory node, allowing cancer cells to evade apoptosis by promoting the translation of pro-survival proteins from IRES-containing mRNAs.

ACS Style

Joseph Ross; Keiran Vanden Dungen; Kamiko R. Bressler; Mikayla Fredriksen; Divya Khandige Sharma; Nirujah Balasingam; Nehal Thakor. Eukaryotic initiation factor 5B (eIF5B) provides a critical cell survival switch to glioblastoma cells via regulation of apoptosis. Cell Death & Disease 2019, 10, 1 -15.

AMA Style

Joseph Ross, Keiran Vanden Dungen, Kamiko R. Bressler, Mikayla Fredriksen, Divya Khandige Sharma, Nirujah Balasingam, Nehal Thakor. Eukaryotic initiation factor 5B (eIF5B) provides a critical cell survival switch to glioblastoma cells via regulation of apoptosis. Cell Death & Disease. 2019; 10 (2):1-15.

Chicago/Turabian Style

Joseph Ross; Keiran Vanden Dungen; Kamiko R. Bressler; Mikayla Fredriksen; Divya Khandige Sharma; Nirujah Balasingam; Nehal Thakor. 2019. "Eukaryotic initiation factor 5B (eIF5B) provides a critical cell survival switch to glioblastoma cells via regulation of apoptosis." Cell Death & Disease 10, no. 2: 1-15.

Journal article
Published: 13 December 2018 in International Journal of Molecular Sciences
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A variety of cellular stresses lead to global translation attenuation due to phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2), which decreases the availability of the eIF2-GTP-Met-tRNAi ternary complex. However, a subset of mRNAs continues to be translated by non-canonical mechanisms under these conditions. In fact, although translation initiation of activating transcription factor 4 (ATF4) is normally repressed by an upstream open reading frame (uORF), a decreased availability of ternary complex leads to increased translation of the main ATF4-coding ORF. We show here that siRNA-mediated depletion of eIF5B—which can substitute for eIF2 in delivering Met-tRNAi—leads to increased levels of ATF4 protein in mammalian cells. This de-repression is not due to phosphorylation of eIF2α under conditions of eIF5B depletion. Although eIF5B depletion leads to a modest increase in the steady-state levels of ATF4 mRNA, we show by polysome profiling that the depletion of eIF5B enhances ATF4 expression primarily at the level of translation. Moreover, eIF5B silencing increases the expression of an ATF4-luciferase translational reporter by a mechanism requiring the repressive uORF2. Further experiments suggest that eIF5B cooperates with eIF1A and eIF5, but not eIF2A, to facilitate the uORF2-mediated repression of ATF4 translation.

ACS Style

Joseph A. Ross; Kamiko R. Bressler; Nehal Thakor. Eukaryotic Initiation Factor 5B (eIF5B) Cooperates with eIF1A and eIF5 to Facilitate uORF2-Mediated Repression of ATF4 Translation. International Journal of Molecular Sciences 2018, 19, 4032 .

AMA Style

Joseph A. Ross, Kamiko R. Bressler, Nehal Thakor. Eukaryotic Initiation Factor 5B (eIF5B) Cooperates with eIF1A and eIF5 to Facilitate uORF2-Mediated Repression of ATF4 Translation. International Journal of Molecular Sciences. 2018; 19 (12):4032.

Chicago/Turabian Style

Joseph A. Ross; Kamiko R. Bressler; Nehal Thakor. 2018. "Eukaryotic Initiation Factor 5B (eIF5B) Cooperates with eIF1A and eIF5 to Facilitate uORF2-Mediated Repression of ATF4 Translation." International Journal of Molecular Sciences 19, no. 12: 4032.

Video audio media
Published: 10 May 2018 in Journal of Visualized Experiments
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Translation initiation is the rate-limiting step of protein synthesis and represents a key point at which cells regulate their protein output. Regulation of protein synthesis is the key to cellular stress-response, and dysregulation is central to many disease states, such as cancer. For instance, although cellular stress leads to the inhibition of global translation by attenuating cap-dependent initiation, certain stress-response proteins are selectively translated in a cap-independent manner. Discreet RNA regulatory elements, such as cellular internal ribosome entry sites (IRESes), allow for the translation of these specific mRNAs. Identification of such mRNAs, and the characterization of their regulatory mechanisms, have been a key area in molecular biology. Toeprinting is a method for the study of RNA structure and function as it pertains to translation initiation. The goal of toeprinting is to assess the ability of in vitro transcribed RNA to form stable complexes with ribosomes under a variety of conditions, in order to determine which sequences, structural elements, or accessory factors are involved in ribosome binding—a pre-cursor for efficient translation initiation. Alongside other techniques, such as western analysis and polysome profiling, toeprinting allows for a robust characterization of mechanisms for the regulation of translation initiation.

ACS Style

Joseph A. Ross; Nehal Thakor. Toeprinting Analysis of Translation Initiation Complex Formation on Mammalian mRNAs. Journal of Visualized Experiments 2018, e57519 -e57519.

AMA Style

Joseph A. Ross, Nehal Thakor. Toeprinting Analysis of Translation Initiation Complex Formation on Mammalian mRNAs. Journal of Visualized Experiments. 2018; (135):e57519-e57519.

Chicago/Turabian Style

Joseph A. Ross; Nehal Thakor. 2018. "Toeprinting Analysis of Translation Initiation Complex Formation on Mammalian mRNAs." Journal of Visualized Experiments , no. 135: e57519-e57519.

Review article
Published: 19 December 2016 in Journal of Nucleic Acids
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Protein synthesis can be segmented into distinct phases comprising mRNA translation initiation, elongation, and termination. Translation initiation is a highly regulated and rate-limiting step of protein synthesis that requires more than 12 eukaryotic initiation factors (eIFs). Extensive evidence shows that the transcriptome and corresponding proteome do not invariably correlate with each other in a variety of contexts. In particular, translation of mRNAs specific to angiogenesis, tumor development, and apoptosis is altered during physiological and pathophysiological stress conditions. In cancer cells, the expression and functions of eIFs are hampered, resulting in the inhibition of global translation and enhancement of translation of subsets of mRNAs by alternative mechanisms. A precise understanding of mechanisms involving eukaryotic initiation factors leading to differential protein expression can help us to design better strategies to diagnose and treat cancer. The high spatial and temporal resolution of translation control can have an immediate effect on the microenvironment of the cell in comparison with changes in transcription. The dysregulation of mRNA translation mechanisms is increasingly being exploited as a target to treat cancer. In this review, we will focus on this context by describing both canonical and noncanonical roles of eIFs, which alter mRNA translation.

ACS Style

Divya Khandige Sharma; Kamiko Bressler; Harshil Patel; Nirujah Balasingam; Nehal Thakor. Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression. Journal of Nucleic Acids 2016, 2016, 1 -19.

AMA Style

Divya Khandige Sharma, Kamiko Bressler, Harshil Patel, Nirujah Balasingam, Nehal Thakor. Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression. Journal of Nucleic Acids. 2016; 2016 ():1-19.

Chicago/Turabian Style

Divya Khandige Sharma; Kamiko Bressler; Harshil Patel; Nirujah Balasingam; Nehal Thakor. 2016. "Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression." Journal of Nucleic Acids 2016, no. : 1-19.

Research paper
Published: 21 February 2016 in RNA Biology
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IRES-mediated translation of key cell fate regulating genes has been implicated in tumorigenesis. Concerted action of canonical eukaryotic initiation factors and IRES transacting factors (ITAFs) was shown to regulate cellular IRES mediated translation; however, the precise molecular mechanism of ribosome recruitment to cellular IRESes remains unclear. Here we show that the X-linked inhibitor of apoptosis (XIAP) IRES operates in an evolutionary conserved viral like mode and the structural integrity, particularly in the vicinity of AUG, is critical for ribosome recruitment. The binding of eIF3 together with PABP potentiates ribosome recruitment to the IRES. Our data support the model in which eIF3 binds directly to the XIAP IRES RNA in a structure-dependent manner and acts as a scaffold for IRES RNA, PABP and the 40S ribosome.

ACS Style

Nehal Thakor; M. Duane Smith; Luc Roberts; Mame Daro Faye; Harshil Patel; Hans-Joachim Wieden; Jamie H. D. Cate; Martin Holcik. Cellular mRNA recruits the ribosome via eIF3-PABP bridge to initiate internal translation. RNA Biology 2016, 14, 553 -567.

AMA Style

Nehal Thakor, M. Duane Smith, Luc Roberts, Mame Daro Faye, Harshil Patel, Hans-Joachim Wieden, Jamie H. D. Cate, Martin Holcik. Cellular mRNA recruits the ribosome via eIF3-PABP bridge to initiate internal translation. RNA Biology. 2016; 14 (5):553-567.

Chicago/Turabian Style

Nehal Thakor; M. Duane Smith; Luc Roberts; Mame Daro Faye; Harshil Patel; Hans-Joachim Wieden; Jamie H. D. Cate; Martin Holcik. 2016. "Cellular mRNA recruits the ribosome via eIF3-PABP bridge to initiate internal translation." RNA Biology 14, no. 5: 553-567.

Book chapter
Published: 21 March 2012 in Affinity Chromatography
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ACS Style

Nehal Thakor; Nehal Thakor And Martin Holcik. RNA Affinity Chromatography. Affinity Chromatography 2012, 1 .

AMA Style

Nehal Thakor, Nehal Thakor And Martin Holcik. RNA Affinity Chromatography. Affinity Chromatography. 2012; ():1.

Chicago/Turabian Style

Nehal Thakor; Nehal Thakor And Martin Holcik. 2012. "RNA Affinity Chromatography." Affinity Chromatography , no. : 1.