Mechanisms of translation regulation by a ribosome-binding factor GCN1L1

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08616
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Hirosaki University
• Principal Investigator: Yamazaki Hiromi 弘前大学, 医学研究科, 助教 (20720915)
• Co-Investigator(Kenkyū-buntansha): 松宮 朋穂 弘前大学, 医学研究科, 助教 (30344592)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: アミノ酸飢餓 / 翻訳制御 / ストレス応答

Outline of Final Research Achievements

The stress response at the translational level is an energetically cost-saving mechanism because translation consumes a considerable amount of energy. Upon exposure to stresses such as that from amino acid starvation (AAS), the translational initiation factor eIF2α is phosphorylated, which represses general translation. At the same time, eIF2α phosphorylation increases the selective translation of cytoprotective proteins, such as ATF4, that transcriptionally activate the stress-response genes. Among four eIF2α kinases, GCN2 responds to AAS and phosphorylates eIF2α. In yeast, Gcn1 is required for Gcn2 activation by AAS, but the roles of GCN1 in mammals remain to be established. Here, we show that GCN1 not only regulates the eIF2α-mediated stress response but also the cell cycle and cell proliferation in a GCN2-independent manner. Taking these findings together, we propose that GCN1 integrates cellular information and coordinates the cellular stress response to enhance viability.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

Gcn1変異マウスは、胎生期における成長遅延と出生直後の呼吸不全による致死性を示したが、Gcn2欠失マウスは正常に出生することが報告されている。Gcn1変異マウス由来の線維芽細胞は細胞増殖の低下とG2/M期細胞の増加を示すことから、GCN1はGCN2非依存性の細胞増殖制御を行うことで正常な胚発生に寄与することを遺伝学的に証明することができた。またGcn1変異マウスは、胎仔期・出生直後に重篤な表現型を示すことから、奇形、胎仔の発育不全、新生児呼吸窮迫症候群のモデルマウスとしての活用が期待される。