Neuronal BC RNAs cooperate with eIF4B to mediate activity-dependent translational control

Eom, Taesun; Muslimov, Ilham A.; Tsokas, Panayiotis; Berardi, Valerio; Zhong, Jun; Tiedge, Henri

doi:10.1083/jcb.201401005

Cited by 52 publications

(79 citation statements)

References 54 publications

(122 reference statements)

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“…Those observations suggest a model in which eIF4B phosphorylation promotes the recruitment of ribosomes to mRNA and, consequently, protein synthesis. Intriguingly, the same eIF4B phosphorylation suppresses neuronal protein synthesis because eIF4B binds to regulatory nonprotein-coding brain cytoplasmic RNAs with high affinity, and is thus sequestered from initiating translation of other proteincoding transcripts (28). It will be extremely interesting to study how eIF4B phosphorylation regulates protein synthesis in different cell types.…”

Section: Discussionmentioning

confidence: 99%

Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival

Wang

Begley

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The protein kinase maternal and embryonic leucine zipper kinase (MELK) is critical for mitotic progression of cancer cells; however, its mechanisms of action remain largely unknown. By combined approaches of immunoprecipitation/mass spectrometry and peptide library profiling, we identified the eukaryotic translation initiation factor 4B (eIF4B) as a MELK-interacting protein during mitosis and a bona fide substrate of MELK. MELK phosphorylates eIF4B at Ser406, a modification found to be most robust in the mitotic phase of the cell cycle. We further show that the MELKeIF4B signaling axis regulates protein synthesis during mitosis. Specifically, synthesis of myeloid cell leukemia 1 (MCL1), an antiapoptotic protein known to play a role in cancer cell survival during cell division, depends on the function of MELK-elF4B. Inactivation of MELK or eIF4B results in reduced protein synthesis of MCL1, which, in turn, induces apoptotic cell death of cancer cells. Our study thus defines a MELK-eIF4B signaling axis that regulates protein synthesis during mitosis, and consequently influences cancer cell survival.aternal and embryonic leucine zipper kinase (MELK) is a serine/threonine kinase with potential roles in mitosis. Similar to other established mitotic factors, such as Aurora kinases and cyclin B1, MELK demonstrates increased protein abundance during mitosis and is degraded when cells progress into G1 phase (1, 2). Our recent study proposed an essential role of MELK in the mitotic progression of specific cancer cell types, with MELK knockdown resulting in multiple mitotic defects, including G2/M arrest and mitotic cell death (2). Despite these advances, there is a lack of mechanistic understanding of the role of MELK during cell division. An immediate question is the identity of the MELK substrates that mediate its role in mitosis, such as promoting mitotic cell survival.Myeloid cell leukemia 1 (MCL1) is an important negative regulator of apoptosis. Uniquely among the Bcl-2 family, it is turned over rapidly by ubiquitin-mediated proteolysis and must be continuously resupplied by translation (3, 4). Protein abundance of MCL1 decreases during prolonged mitotic arrest induced by antimicrotubule drugs, rendering arrested cells highly sensitive to inhibitors of other Bcl-2 family members (5). We thus speculate that synthesis of MCL1 is important for cell survival during normal and drug-arrested mitosis and, conversely, that a drug that decreases MCL1 synthesis during mitosis might have anticancer potential.The rate of protein synthesis and other basic biological processes, such as DNA or RNA biogenesis, fluctuates throughout the cell cycle. Overall protein synthesis significantly decreases when cells enter mitosis (6, 7), consistent with the notion that macromolecule synthesis predominantly occurs in interphase before the segregation of cellular mass in mitosis.A recent study based on ribosome profiling identified a set of genes that are translationally repressed in mitosis, and proposed that suppressed protein synthesis migh...

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Section: Discussionmentioning

confidence: 99%

Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival

Wang

Begley

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Following their expression, BC200 RNAs immediately migrate to dendrites, where they interact and interfere with various translational initiation factors, including eIF4A, eIF4B, and PABP. [1][2][3][4][5][6][7] BC200 RNA is thought to exert local translational control by forming distinctive microdomains in dendrites, and this is believed to contribute to the maintenance of neuronal plasticity. BC1 RNA is the rodent counterpart of BC200 RNA 3 ; the 2 together comprise the BC RNAs.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of BC200 RNA expression reduces cell migration and invasion by destabilizing mRNA for calcium-binding protein S100A11

et al. 2017

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Although BC200 RNA is best known as a neuron-specific non-coding RNA, it is overexpressed in various cancer cells. BC200 RNA was recently shown to contribute to metastasis in several cancer cell lines, but the underlying mechanism was not understood in detail. To examine this mechanism, we knocked down BC200 RNA in cancer cells, which overexpress the RNA, and examined cell motility, profiling of ribosome footprints, and the correlation between cell motility changes and genes exhibiting altered ribosome profiles. We found that BC200 RNA knockdown reduced cell migration and invasion, suggesting that BC200 RNA promotes cell motility. Our ribosome profiling analysis identified 29 genes whose ribosomal occupations were altered more than 2-fold by BC200 RNA knockdown. Many (> 30%) of them were directly or indirectly related to cancer progression. Among them, we focused on S100A11 (which showed a reduced ribosome footprint) because its expression was previously shown to increase cellular motility. S100A11 was decreased at both the mRNA and protein levels following knockdown of BC200 RNA. An actinomycin-chase experiment showed that BC200 RNA knockdown significantly decreased the stability of the S100A11 mRNA without changing its transcription rate, suggesting that the downregulation of S100A11 was mainly caused by destabilization of its mRNA. Finally, we showed that the BC200 RNAknockdown-induced decrease in cell motility was mainly mediated by S100A11. Together, our results show that BC200 RNA promotes cell motility by stabilizing S100A11 transcripts.

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“…While Ser406 phosphorylation is required for optimal translational activity, it was reported that in neurons eIF4B is rapidly dephosphorylated at Ser406 upon neuronal stimulation to promote neuron-specific translation. In this case Ser406 dephosphorylation causes a decrease in the binding of eIF4B to brain cytoplasmic RNAs (non-protein-coding RNAs), freeing eIF4B for initiation [38]. This rapid eIF4B dephosphorylation was attributed to PP2A, as it was inhibited by 25nM OA (See Table 1).…”

Section: Regulation Of Eif4f Activity By Ser/the Phosphatasesmentioning

confidence: 99%

Serine-threonine protein phosphatases: Lost in translation

Kolupaeva¹

2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Protein synthesis is one of the most complex and energy-consuming processes in eukaryotic cells and therefore is tightly regulated. One of the main mechanisms of translational control is post-translational modifications of the components of translational apparatus. Phosphorylation status of translation factors depends on the balanced action of kinases and phosphatases. While many kinase-dependent events are well defined, phosphatases that counteract phosphorylation are rarely determined. This mini-review focuses on the regulation of activity of translational initiation factors by Serine/Threonine phosphatases.

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Neuronal BC RNAs cooperate with eIF4B to mediate activity-dependent translational control

Abstract: Regulatory brain cytoplasmic RNAs cooperate with eukaryotic initiation factor 4B to couple translation to receptor activation in support of long-term plastic changes in neurons.

Cited by 52 publications

References 54 publications

Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival

Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival

Knockdown of BC200 RNA expression reduces cell migration and invasion by destabilizing mRNA for calcium-binding protein S100A11

Serine-threonine protein phosphatases: Lost in translation

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