YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1

Somasekharan, Syam Prakash; El-Naggar, Amal M.; Leprivier, Gabriel; Cheng, Hongwei; Hajee, Shamil; Grünewald, Thomas G.P.; Zhang, Fan; Ng, Tony; Delattre, Olivier; Evdokimova, Valentina; Wang, Yuzhuo; Gleave, Martin; Sorensen, Poul H.

doi:10.1083/jcb.201411047

Cited by 244 publications

(287 citation statements)

References 70 publications

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“…Moreover, mutations in DDX3 promoting the WNT subclass of pediatric medulloblastoma inhibit the ATPase activity of DDX3, which would be expected to trap mRNPs in stress granules based on analogous mutations in the yeast ortholog Ded1 [58]. Similarly, YB-1 overexpression upregulates G3BP levels in human sarcomas, correlates with poor survival and in mouse models G3BP promotes metastasis [86]. Given the diversity of mechanisms by which stress granules can affect cell signaling and survival under stress conditions, one anticipates that stress granule formation will have multiple roles in both tumor progression and the outcome of chemotherapeutic treatments.…”

Section: Stress Granules In Diseasementioning

confidence: 99%

Principles and Properties of Stress Granules

Protter

Parker

2016

Trends in Cell Biology

1,365

1,274

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Stress granules are assemblies of untranslating mRNPs that form from mRNAs stalled in translation initiation. Stress granules form through interactions between mRNA binding proteins that link together populations of mRNPs. Interactions promoting stress granule formation include conventional protein-protein interactions, as well as interactions involving intrinsically disordered regions of proteins. Assembly and disassembly of stress granules are modulated by a variety of post-translational modifications as well as a number of ATP dependent RNP or protein remodeling complexes, illustrating that stress granules represent an active liquid wherein energy input maintains their dynamic state. Stress granule formation modulates the stress response, viral infection, and signaling pathways. Persistent or aberrant stress granule formation contributes to neurodegenerative disease and some cancers.

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Section: Stress Granules In Diseasementioning

confidence: 99%

Principles and Properties of Stress Granules

Protter

Parker

2016

Trends in Cell Biology

1,365

1,274

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“…For example, AMPK activation can interfere with tumor cell proliferation, notably by affecting translation (Grzmil and Hemmings, 2012;Chen et al, 2014). On the other hand, SGs are formed by some types of cancer, where they promote tumor survival and progression (Thedieck et al, 2013;Somasekharan et al, 2015). Furthermore, SG-like granules are also produced in other diseases that are linked to altered AMPK activities, including type 2 diabetes and neurodegeneration (reviewed in Mahboubi and Stochaj, 2014).…”

Section: Discussionmentioning

confidence: 99%

AMP Kinase Activation Alters Oxidant-Induced Stress Granule Assembly by Modulating Cell Signaling and Microtubule Organization

2016

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Eukaryotic cells assemble stress granules (SGs) when translation initiation is inhibited. Different cell signaling pathways regulate SG production. Particularly relevant to this process is 59-AMPactivated protein kinase (AMPK), which functions as a stress sensor and is transiently activated by adverse physiologic conditions. Here, we dissected the role of AMPK for oxidant-induced SG formation. Our studies identified multiple steps of de novo SG assembly that are controlled by the kinase. Single-cell analyses demonstrated that pharmacological AMPK activation prior to stress exposure changed SG properties, because the granules became more abundant and smaller in size. These altered SG characteristics correlated with specific changes in cell survival, cell signaling, cytoskeletal organization, and the abundance of translation initiation factors. Specifically, AMPK activation increased stress-induced eukaryotic initiation factor (eIF) 2a phosphorylation and reduced the concentration of eIF4F complex subunits eIF4G and eIF4E. At the same time, the abundance of histone deacetylase 6 (HDAC6) was diminished. This loss of HDAC6 was accompanied by increased acetylation of a-tubulin on Lys40. Pharmacological studies further confirmed this novel AMPK-HDAC6 interplay and its importance for SG biology. Taken together, we provide mechanistic insights into the regulation of SG formation. We propose that AMPK activation stimulates oxidant-induced SG formation but limits their fusion into larger granules.

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“…SGs are dense aggregations in the cytoplasm composed of RNA and RNA-binding proteins including GTPase-activating protein (SH3 domain)-binding proteins 1 and 2 (G3BP1 and G3BP2), among others (8,9); they function to protect RNAs from harmful conditions. SGs also function as a decision point for untranslated mRNAs to proceed to further storage, translation reprogramming, or degradation (6,7,10).…”

mentioning

confidence: 99%

Stress granule-associated protein G3BP2 regulates breast tumor initiation

Gupta

Badeaux

Liu

et al. 2017

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

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Breast tumors contain tumorigenic cancer cells, termed “tumor-initiating cells” (TICs), which are capable of both replenishing themselves and giving rise to populations of nontumorigenic breast cancer cells (non-TICs). However, the molecular mechanisms responsible for breast tumor initiation remain poorly understood. Here we describe a chemical screening strategy to identify small molecules that enhance the effect of chemotherapeutic agents on TIC-enriched breast cancer cells. We identified proteins that interact with the lead compound C108, including the stress granule-associated protein, GTPase-activating protein (SH3 domain)-binding protein 2, G3BP2. G3BP2 regulates breast tumor initiation through the stabilization of Squamous cell carcinoma antigen recognized by T cells 3 (SART3) mRNA, which leads to increased expression of the pluripotency transcription factors Octamer-binding protein 4 (Oct-4) and Nanog Homeobox (Nanog). Our findings suggest that G3BP2 is important for the process of breast cancer initiation. Furthermore, these data suggest a possible connection between stress granule formation and tumor initiation in breast cancer cells.

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YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1

Abstract: YB-1, which is upregulated in human sarcomas, controls the availability of the stress granule nucleator G3BP1 and thereby controls stress granule assembly.

Cited by 244 publications

References 70 publications

Principles and Properties of Stress Granules

Principles and Properties of Stress Granules

AMP Kinase Activation Alters Oxidant-Induced Stress Granule Assembly by Modulating Cell Signaling and Microtubule Organization

Stress granule-associated protein G3BP2 regulates breast tumor initiation

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