title: YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1.
abstract: Under cell stress, global protein synthesis is inhibited to preserve energy. One mechanism is to sequester and silence mRNAs in ribonucleoprotein complexes known as stress granules (SGs), which contain translationally silent mRNAs, preinitiation factors, and RNA-binding proteins. Y-box binding protein 1 (YB-1) localizes to SGs, but its role in SG biology is unknown. We now report that YB-1 directly binds to and translationally activates the 5' untranslated region (UTR) of G3BP1 mRNAs, thereby controlling the availability of the G3BP1 SG nucleator for SG assembly. YB-1 inactivation in human sarcoma cells dramatically reduces G3BP1 and SG formation in vitro. YB-1 and G3BP1 expression are highly correlated in human sarcomas, and elevated G3BP1 expression correlates with poor survival. Finally, G3BP1 down-regulation in sarcoma xenografts prevents in vivo SG formation and tumor invasion, and completely blocks lung metastasis in mouse models. Together, these findings demonstrate a critical role for YB-1 in SG formation through translational activation of G3BP1, and highlight novel functions for SGs in tumor progression.
authors: Department of Pathology and Laboratory Medicine and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Syam Prakash
authors: SP
authors: Somasekharan
authors: Department of Pathology and Laboratory Medicine and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Amal
authors: A
authors: El-Naggar
authors: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Gabriel
authors: G
authors: Leprivier
authors: Department of Pathology and Laboratory Medicine and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors: Hongwei
authors: H
authors: Cheng
authors: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Shamil
authors: S
authors: Hajee
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 830, Genetics and Biology of Cancers, Institute Curie Research Center, 75248 Paris, France.
authors: Thomas G P
authors: TG
authors: Grunewald
authors: Department of Pathology and Laboratory Medicine and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors: Fan
authors: F
authors: Zhang
authors: Department of Pathology and Laboratory Medicine and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors: Tony
authors: T
authors: Ng
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 830, Genetics and Biology of Cancers, Institute Curie Research Center, 75248 Paris, France.
authors: Olivier
authors: O
authors: Delattre
authors: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Valentina
authors: V
authors: Evdokimova
authors: Department of Pathology and Laboratory Medicine and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors: Yuzhuo
authors: Y
authors: Wang
authors: Department of Pathology and Laboratory Medicine and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors: Martin
authors: M
authors: Gleave
authors: Department of Pathology and Laboratory Medicine and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada Department of Pathology and Laboratory Medicine and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada psor@mail.ubc.ca.
authors: Poul H
authors: PH
authors: Sorensen
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D003594:Cytoplasmic Granules / Q000235:genetics*; D004265:DNA Helicases; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018384:Oxidative Stress / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000235:genetics*; D020365:RNA Helicases; D034622:RNA Interference; D000067776:RNA Recognition Motif Proteins; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000378:metabolism; D012509:Sarcoma / Q000473:pathology; D013312:Stress, Physiological / Q000235:genetics*; D051840:Y-Box-Binding Protein 1 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D002352:Carrier Proteins; D019394:Ki-67 Antigen; D000075223:Poly-ADP-Ribose Binding Proteins; D000067776:RNA Recognition Motif Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases