title: Inhibition of nonsense-mediated RNA decay by the tumor microenvironment promotes tumorigenesis.
abstract: While nonsense-mediated RNA decay (NMD) is an established mechanism to rapidly degrade select transcripts, the physiological regulation and biological significance of NMD are not well characterized. We previously demonstrated that NMD is inhibited in hypoxic cells. Here we show that the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α) translation initiation factor by a variety of cellular stresses leads to the inhibition of NMD and that eIF2α phosphorylation and NMD inhibition occur in tumors. To explore the significance of this NMD regulation, we used an unbiased approach to identify approximately 750 NMD-targeted mRNAs and found that these mRNAs are overrepresented in stress response and tumor-promoting pathways. Consistent with these findings, the inhibition of NMD promotes cellular resistance to endoplasmic reticulum stress and encourages tumor formation. The transcriptional and translational regulations of gene expression by the microenvironment are established mechanisms by which tumor cells adapt to stress. These data indicate that NMD inhibition by the tumor microenvironment is also an important mechanism to dynamically regulate genes critical for the response to cellular stress and tumorigenesis.
authors: Department of Medicine, New York University School of Medicine, 550 1st Avenue, New York, New York 10016, USA.
authors: Ding
authors: D
authors: Wang
authors: Jiri
authors: J
authors: Zavadil
authors: Leenus
authors: L
authors: Martin
authors: Fabio
authors: F
authors: Parisi
authors: Eugene
authors: E
authors: Friedman
authors: David
authors: D
authors: Levy
authors: Heather
authors: H
authors: Harding
authors: David
authors: D
authors: Ron
authors: Lawrence B
authors: LB
authors: Gardner
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018389:Codon, Nonsense / Q000235:genetics*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020365:RNA Helicases; D034622:RNA Interference; D020871:RNA Stability; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D015852:Eukaryotic Initiation Factor-2; D015534:Trans-Activators; D020365:RNA Helicases; C101828:UPF1 protein, human