EIF4EBP1
EIF4EBP1（eukaryotic translation initiation factor 4E-binding protein 1）または4E-BP1は、ヒトではEIF4EBP1遺伝子にコードされるタンパク質である[5]。4E-BP1は翻訳開始因子eIF4Eに結合することでキャップ依存的翻訳を阻害する。4E-BP1はリン酸化によってeIF4Eから放出され、その結果キャップ依存的翻訳が継続されてタンパク質合成速度が高まる[6]。
リン酸化
[編集]リン酸化された4E-BP1は、上流のシグナル伝達（mTORシグナル）の活性化のマーカーとなると考えられている。4E-BP1には7カ所のリン酸化部位が存在し、中でも重要なのはリン酸化の開始部位であるThr37/Thr46、2番目の部位であるThr70、そして最終部位であるSer65である。しかしながら、Ser65とThr70のリン酸化だけでは4E-BP1による翻訳阻害の遮断には不十分であり、複数のリン酸化イベントが組み合わさることでタンパク質合成速度の上昇が引き起こされていることが示唆されている[7]。
機能
[編集]4E-BP1はeIF4Eと直接相互作用する。eIF4Eは、リボソーム40SサブユニットをmRNAの5'末端へリクルートするタンパク質複合体（eIF4F）の限定因子となっている。4E-BP1とeIF4Eの相互作用により、この複合体の組み立てが阻害され、翻訳は抑制される。4E-BP1のリン酸化は紫外線照射やインスリンシグナルなどさまざまなシグナルに応答して生じ、eIF4Eからの解離を引き起こしてキャップ依存的翻訳を活性化する[8]。
4E-BP1の高レベルのリン酸化はヒトのがんで幅広く報告されており、そのいくつかでは予後不良と関係している[9]。
相互作用
[編集]4E-BP1は次に挙げる因子と相互作用することが示されている。
- eIF4E[10][11][12][13][14][15][16][17][18][19][20][21][22]
- RPTOR[14][23][24][25][26][27][28][29]
- mTOR[23][24][25][26][30][31][32][33]
出典
[編集]- ^ a b c GRCh38: Ensembl release 89: ENSG00000187840 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031490 - Ensembl, May 2017
- ^ Human PubMed Reference:
- ^ Mouse PubMed Reference:
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- ^ Pause, Arnim; Belsham, Graham J.; Gingras, Anne-Claude; Donzé, Olivier; Lin, Tai-An; Lawrence, John C.; Sonenberg, Nahum (1994-10-27). “Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function”. Nature 371 (6500): 762–767. doi:10.1038/371762a0. ISSN 0028-0836.
- ^ Gingras, Anne-Claude; Raught, Brian; Gygi, Steven P.; Niedzwiecka, Anna; Miron, Mathieu; Burley, Stephen K.; Polakiewicz, Roberto D.; Wyslouch-Cieszynska, Aleksandra et al. (2001-11-01). “Hierarchical phosphorylation of the translation inhibitor 4E-BP1”. Genes & Development 15 (21): 2852–2864. doi:10.1101/gad.912401. ISSN 0890-9369.
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- ^ “Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells”. Mol. Cell. Biol. 26 (10): 3955–65. (May 2006). doi:10.1128/MCB.26.10.3955-3965.2006. PMC 1489005. PMID 16648488.
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関連文献
[編集]- “4E-binding protein 1: a key molecular "funnel factor" in human cancer with clinical implications”. Cancer Res. 67 (16): 7551–7555. (2007). doi:10.1158/0008-5472.CAN-07-0881. PMID 17699757.
- “The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins”. Mol. Cell. Biol. 15 (9): 4990–7. (1995). doi:10.1128/MCB.15.9.4990. PMC 230746. PMID 7651417.
- “Phosphorylation of PHAS-I by mitogen-activated protein (MAP) kinase. Identification of a site phosphorylated by MAP kinase in vitro and in response to insulin in rat adipocytes”. J. Biol. Chem. 269 (37): 23185–91. (1994). doi:10.1016/S0021-9258(17)31637-X. PMID 8083223.
- “Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E”. EMBO J. 14 (22): 5701–9. (1996). doi:10.1002/j.1460-2075.1995.tb00257.x. PMC 394685. PMID 8521827.
- “Cap-binding protein (eukaryotic initiation factor 4E) and 4E-inactivating protein BP-1 independently regulate cap-dependent translation”. Mol. Cell. Biol. 16 (10): 5450–7. (1996). doi:10.1128/MCB.16.10.5450. PMC 231545. PMID 8816458.
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- “Identification of phosphorylation sites in the translational regulator, PHAS-I, that are controlled by insulin and rapamycin in rat adipocytes”. J. Biol. Chem. 272 (15): 10240–10247. (1997). doi:10.1074/jbc.272.15.10240. PMID 9092573.
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- “Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR”. FEBS Lett. 453 (3): 387–390. (1999). doi:10.1016/S0014-5793(99)00762-0. PMID 10405182.
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