ヤマウチ　カヅヨ   YAMAUCHI Kadzuyo   山内　かづ代    所属   医学部 医学科    職種   評議員
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	The unfolded protein response is a major mechanism by which LRP1 regulates Schwann cell survival after injury.
掲載誌名	正式名：The Journal of neuroscience : the official journal of the Society for Neuroscience 略　 称：J Neurosci ISSNコード：(1529-2401)0270-6474(Linking)
掲載区分	国外
巻・号・頁	31(38),pp.13376-85
著者・共著者	Mantuano Elisabetta, Henry Kenneth, Yamauchi Tomonori, Hiramatsu Nobuhiko, Yamauchi Kazuyo, Orita Sumihisa, Takahashi Kazuhisa, Lin Jonathan H, Gonias Steven L, Campana W Marie
発行年月	2011/09
概要	In peripheral nerve injury, Schwann cells (SCs) must survive to exert a continuing and essential role in successful nerve regeneration. Herein, we show that peripheral nerve injury is associated with activation of endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR). The UPR culminates in expression of C/EBP homology protein (CHOP), a proapoptotic transcription factor in SCs, unless counteracted by LDL receptor-related protein-1 (LRP1), which serves as a major activator of phosphatidylinositol 3-kinase (PI3K). Sciatic nerve crush injury in rats induced expression of the ER chaperone GRP78/BIP, reflecting an early, corrective phase of the UPR. However, when LRP1 signaling was inhibited with receptor-associated protein, PI3K activity was decreased and CHOP protein expression increased, particularly in myelinating SCs. In cultured SCs, the PKR-like ER kinase target eIF2α was phosphorylated and CHOP was induced by (1) inhibiting PI3K, (2) treating the cells with tumor necrosis factor-α (TNF-α), or (3) genetic silencing of LRP1. CHOP gene deletion in SCs decreased cell death in response to TNF-α. Furthermore, the effects of TNF-α on phosphorylated eIF2α, CHOP, and SC death were blocked by adding LRP1 ligands that augment LRP1-dependent cell signaling to PI3K. Collectively, our results support a model in which UPR-activated signaling pathways represent a major challenge to SC survival in nerve injury. LRP1 functions as a potent activator of PI3K in SCs and, by this mechanism, limits SC apoptosis resulting from increased CHOP expression in nerve injury.
DOI	10.1523/JNEUROSCI.2850-11.2011
PMID	21940431