Translational Repression of G3BP in Cancer and Germ Cells Suppresses Stress Granules and Enhances Stress Tolerance

Lee, Anna K.; Klein, Jonathon; Tacer, Klementina Fon; Lord, Tessa; Oatley, Melissa J.; Porter, Shaina N.; Pruett-Miller, Shondra M.; Tikhonova, Elena B.; Karamyshev, Andrey L.; Wang, Yongdong; Yang, Peiguo; Korff, Ané; Kim, Hong Joo; Taylor, J. Paul; Potts, Patrick Ryan

doi:10.1016/j.molcel.2020.06.037

Cited by 46 publications

(48 citation statements)

References 66 publications

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“…In this regulation P-bodies have a major impact on chromatin remodeling, in line with previous findings indicating that the P-body transcriptome contains mRNA encoding chromatin-regulatory factors [79]. In testis spermatogonial stem cells, MAGE-B2 interacts with and represses G3BP1 mRNA translation, which reduces SG formation [142]. Intriguingly, this reduction is associated with increased tolerance to heat stress, suggesting that SG accumulation in these cells is harmful.…”

Section: Box 1 Rnp Granule Functions Beyond Cancer Cellssupporting

confidence: 87%

Cancer cell adaptability: turning ribonucleoprotein granules into targets

et al. 2021

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Stress granules (SGs) and processing bodies (P-bodies) are membraneless cytoplasmic condensates of ribonucleoproteins (RNPs). They both regulate RNA fate under physiological and pathological conditions, and are thereby involved in the regulation and maintenance of cellular integrity. During tumorigenesis, cancer cells use these granules to thrive, to adapt to the harsh conditions of the tumor microenvironment (TME), and to protect themselves from anticancer treatments. This ability to provide multiple outcomes not only makes RNP granules promising targets for cancer therapy but also emphasizes the need for more knowledge about the biology of these granules to achieve clinical use. In this review we focus on the role of RNP granules in cancer, and on how their composition and regulation might be used to elaborate therapeutic strategies. RNP granules between stress and translationRegulating the expression of the genomic information is crucial to ensure cell identity and functionality. During transformation into cancer cells and throughout tumor progression, cells dynamically modulate the expression of their genomic information to adapt to environmental cues. Control of mRNA translation ensures the spatiotemporal adjustment of protein synthesis, and is often dysregulated in cancer cells to favor their adaptability [1]. In particular, regulation of translation initiation allows cancer cells to reprogram this activity towards essential mRNAs, such as those encoding oncogenes, to facilitate cell growth, proliferation, and survival [2]. Moreover, cancer cells must adapt to stress conditions in the TME, mainly through activation of the integrated stress response (ISR) [3,4] (Figure 1). This pathway controls translation initiation through eukaryotic initiation factor 2 (eIF2), which, once phosphorylated on its α subunit, prevents the formation of the ternary complex (eIF2:GTP: methionyl-initiator-tRNA) and consequently blocks translation initiation [5]. Four stress-sensor kinases can induce eIF2α phosphorylation, namely the PKR-like endoplasmic reticulum kinase (PERK), general control nonrepressible 2 (GCN2), heme-regulated inhibitor (HRI), and protein kinase R (PKR). The outcome of ISR activation is a global decrease in protein synthesis, while sparing the translation of some specific mRNAs such as that of transcription factor ATF4 [4]. Activation of this pathway, and the resulting selective translation, favor tumor progression following endoplasmic reticulum stress caused for instance by the hypoxic TME [6]. Furthermore, ISR activation by aberrant MYC expression enables cancer cells to adapt to this intrinsic stress by reprogramming translational programs. Consequently, the ISR prevents cancer cells from entering apoptosis and promotes both tumor progression [7,8] and escape from antitumor immunity [9,10].

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Section: Box 1 Rnp Granule Functions Beyond Cancer Cellssupporting

confidence: 87%

Cancer cell adaptability: turning ribonucleoprotein granules into targets

et al. 2021

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“…Upon removal of the stimulus, SGs depolymerize through microtubules and dynein to release the wrapped mRNA and proteins, and restore normal mRNA translation 9 . Recent studies have demonstrated that dynamical SG is a mechanism involved in cellular protection 10‐12 . When disturbed by specific server adverse factors, SGs can promote cell apoptosis through stress‐activated pathways 13 .…”

Section: Introductionmentioning

confidence: 99%

Response to stress in biological disorders: Implications of stress granule assembly and function

Wang

Yang

et al. 2021

Cell Proliferation

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It is indispensable for cells to adapt and respond to environmental stresses, in order for organisms to survive. Stress granules (SGs) are condensed membrane‐less organelles dynamically formed in the cytoplasm of eukaryotes cells to cope with diverse intracellular or extracellular stress factors, with features of liquid‐liquid phase separation. They are composed of multiple constituents, including translationally stalled mRNAs, translation initiation factors, RNA‐binding proteins and also non‐RNA‐binding proteins. SG formation is triggered by stress stimuli, viral infection and signal transduction, while aberrant assembly of SGs may contribute to tissue degenerative diseases. Recently, a growing body of evidence has emerged on SG response mechanisms for cells facing high temperatures, oxidative stress and osmotic stress. In this review, we aim to summarize factors affecting SGs assembly, present the impact of SGs on germ cell development and other biological processes. We particularly emphasize the significance of recently reported RNA modifications in SG stress responses. In parallel, we also review all current perspectives on the roles of SGs in male germ cells, with a particular focus on the dynamics of SG assembly.

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“…MAGE‐B2 and DDX5 have recently been demonstrated to regulate G3BP1 transcripts in an antagonistic manner. MAGE‐B2, a protein member of the Melanoma antigen (MAGE) family, binds the G3BP1 mRNA 5’UTR to reduce its translation, whereas the Dead‐box RNA helicase DDX5 (or p68) binds to the G3BP1 5’UTR to increase translation (Lee et al, 2020). Interestingly, DDX5 binding to G3BP1 is inversely correlated with MAGE‐B2 binding and the deletion of the DDX5‐binding sequence in G3BP1 5’UTR inhibits MAGE‐B2 binding to G3BP1 , suggesting that the two proteins compete for the same sequence (Lee et al, 2020).…”

Section: Regulation Of G3bp1 Mrnamentioning

confidence: 99%

The multi‐functional RNA‐binding protein G3BP1 and its potential implication in neurodegenerative disease

Sidibé

Dubinski

Velde

2021

Journal of Neurochemistry

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Since its discovery in 1996 as a RAS-binding partner, Ras-GTPaseactivating protein (GAP)-binding protein 1 (G3BP1) has been linked to a variety of biological processes, molecular functions and cellular compartments (Parker et al., 1996). Initially suggested to play a key role in the Ras signaling pathway via direct binding to Ras, more recent evidence contradicts this potential function (Annibaldi et al., 2011;Xu et al., 2013). Even if this initial function is debated, based on its role in development, RNA metabolism, degradation and stress response, G3BP1 seems to be a jack-of-all-trades protein that is fundamental to cellular homeostasis.

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Translational Repression of G3BP in Cancer and Germ Cells Suppresses Stress Granules and Enhances Stress Tolerance

Cited by 46 publications

References 66 publications

Cancer cell adaptability: turning ribonucleoprotein granules into targets

Cancer cell adaptability: turning ribonucleoprotein granules into targets

Response to stress in biological disorders: Implications of stress granule assembly and function

The multi‐functional RNA‐binding protein G3BP1 and its potential implication in neurodegenerative disease

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