title: A novel transmembrane protein defines the endoplasmic reticulum stress-induced cell death pathway.
abstract: Mitochondrial membrane potential (ΔΨm) maintenance is physiologically critical in cells; its loss causes apoptotic signalling and cell death. Accumulating DNA mutations and unfolded proteins in stressed cells activate signalling pathways for cell death induction. Cancer cells often fail to die even in the presence of some death signalling proteins. Here, we report a short hairpin RNA (shRNA) with an artificial sequence, denoted Psi1 shRNA, which leads to ΔΨmloss in HCT116 cells. The Psi1 shRNA target gene was shown to encode transmembrane protein 117 (TMEM117). TMEM117 knockdown led to ΔΨmloss, increased reactive oxygen species levels, up-regulation of an endoplasmic reticulum (ER) stress sensor C/EBP homologous protein and active caspase-3 expression, and cell growth impairment, altering homeostasis towards cell death. TMEM117 levels were down-regulated in response to the ER stressor thapsigargin and decreased when cells showed ΔΨmloss. These results suggested that TMEM117 RNAi allowed apoptotic cell death. Therefore, TMEM117 probably mediates the signalling of ΔΨmloss in ER stress-mediated mitochondria-mediated cell death.
authors.affiliation: Graduate School of Bionics, Tokyo University of Technology, 1401-1 Katakura-machi, Hachioji, Tokyo 192-0982, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Tamaki
authors.affiliation: Graduate School of Bionics, Tokyo University of Technology, 1401-1 Katakura-machi, Hachioji, Tokyo 192-0982, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Kamatsuka
authors.affiliation: Graduate School of Bionics, Tokyo University of Technology, 1401-1 Katakura-machi, Hachioji, Tokyo 192-0982, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Sato
authors.affiliation: Graduate School of Bionics, Tokyo University of Technology, 1401-1 Katakura-machi, Hachioji, Tokyo 192-0982, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Morooka
authors.affiliation: Graduate School of Bionics, Tokyo University of Technology, 1401-1 Katakura-machi, Hachioji, Tokyo 192-0982, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Otsuka
authors.affiliation: RNAi Inc., 4-1-4 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hattori
authors.affiliation: Graduate School of Bionics, Tokyo University of Technology, 1401-1 Katakura-machi, Hachioji, Tokyo 192-0982, Japan. Electronic address: tsugiyama@stf.teu.ac.jp.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Sugiyama
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C000620506:TMEM117 protein, human; D019284:Thapsigargin; D053148:Caspase 3
keywords: Cell death; Endoplasmic reticulum stress; Mitochondrial membrane potential; RNAi