CPEB1 regulates the expression of MTDH/AEG-1 and glioblastoma cell migration.
Cytoplasmic polyadenylation element-binding protein 1 (CPEB1) is an mRNA-binding protein present in both neurons and glia. CPEB1 is capable of both repressing mRNA translation and activating it depending upon its phosphorylation state. CPEB1-bound mRNAs are held in translational dormancy until CPEB1 is phosphorylated, leading to the cytoplasmic polyadenylation of the bound mRNA that triggers translation. Here, we show that CPEB1 can bind to and regulate translation of the mRNA-encoding metadherin (MTDH, also known as AEG-1 and Lyric) in the rat glioblastoma cell line CNS1. MTDH/AEG-1 is being revealed as a critical signaling molecule in tumor progression, playing roles in invasion, metastasis, and chemoresistance. By using a mutant of CPEB1 that cannot be phosphorylated (thereby holding target mRNAs in translational arrest), we show that inhibiting CPEB1-mediated translation blocks MTDH/AEG-1 expression in vitro and inhibits glioblastomas tumor growth in vivo. CPEB1-mediated translation is likely to impact several signaling pathways that may promote tumor progression, but we present evidence suggesting a role in directed cell migration in glioblastoma cells. In addition, reporter mRNA containing CPEB1-binding sites is transported to the leading edge of migrating cells and translated, whereas the same mRNA with point mutations in the binding sites is synthesized perinuclearly. Our findings show that CPEB1 is hyperactive in rat glioblastoma cells and is regulating an important cohort of mRNAs whose increased translation is fueling the progression of tumor proliferation and dispersal in the brain. Thus, targeting CPEB1-mediated mRNA translation might be a sound therapeutic approach.
Department of Molecular, Cellular & Developmental Biology, 260 Whitney Ave, KBT 338, Box 208103, New Haven, CT 06520, USA.
Dawn M
DM
Kochanek
David G
DG
Wells
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics / Q000378:metabolism*
C490386:CPEB1 protein, human; C539243:CPEB1 protein, rat; D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D039221:mRNA Cleavage and Polyadenylation Factors