2012年8月17日 讯 /生物谷BIOON/ --我们机体中的细胞不断进行着破碎-死亡-再生的过程,相比自相残杀,细胞中的蛋白质常常会破碎分裂成为细胞的氨基酸组分,其扮演着细胞生长和更新的结构单元的作用。但是一旦这个过程发生破坏就会引发严重的疾病,最典型的就是癌症,癌细胞可以无限制增殖,但是其细胞自我消化的能力却是非常缓慢乃至停滞的。
众所周知,调节细胞生长的生长因子可以刺激机体中新蛋白质的合成,进而促进细胞的生长和分裂。近日,来自麦吉尔大学的研究者首次揭示了,为了获得细胞蛋白质合成所需的氨基酸的供给,生长因子可以通过调节/刺激作用来增加细胞中蛋白质的破损,从而来产生游离的氨基酸以产生新的蛋白质。这种氨基酸的重复利用确保了细胞可以以最佳的状态来适应环境。相关研究成果刊登在了近日的国际杂志Journal of Biological Chemistry上。
新研究发现的这个细胞过程,就好比是我们要盖房子,必须有充足的木材来作为原料,以确保我们木材的可用以及持续性以免发生木材不够用的情况。通过研究大鼠的肝脏细胞,研究者揭示了生长因子可以促进细胞酸化的作用,这种酸化作用将会导致细胞中蛋白质的分解并游离为氨基酸,以保证细胞维持健康生长所必须的氨基酸。
这项研究或许为开发癌症及糖尿病的疗法提供帮助,同时也指出了开发抵御某些疾病的新型药物的前景。(生物谷Bioon.com)
编译自:Coordinated protein breakdown and synthesis: a key to healthy growth of cells
doi:10.1074/jbc.M112.352229
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Epidermal Growth Factor-induced Vacuolar (H+)-ATPase Assembly A ROLE IN SIGNALING VIA mTORC1 ACTIVATION*
Yanqing Xu‡,1, Amanda Parmar‡,1, Emmanuelle Roux‡, Alejandro Balbis‡, Victor Dumas‡, Stephanie Chevalier§ and Barry I. Posner‡,2
Using proteomics and immunofluorescence, we demonstrated epidermal growth factor (EGF) induced recruitment of extrinsic V1 subunits of the vacuolar (H+)-ATPase (V-ATPase) to rat liver endosomes. This was accompanied by reduced vacuolar pH. Bafilomycin, an inhibitor of V-ATPase, inhibited EGF-stimulated DNA synthesis and mammalian target of rapamycin complex 1 (mTORC1) activation as indicated by a decrease in eukaryotic initiation factor 4E-binding 1 (4E-BP1) phosphorylation and p70 ribosomal S6 protein kinase (p70S6K) phosphorylation and kinase activity. There was no corresponding inhibition of EGF-induced Akt and extracellular signal-regulated kinase (Erk) activation. Chloroquine, a neutralizer of vacuolar pH, mimicked bafilomycin effects. Bafilomycin did not inhibit the association of mTORC1 with Raptor nor did it affect AMP-activated protein kinase activity. Rather, the intracellular concentrations of essential but not non-essential amino acids were decreased by bafilomycin in EGF-treated primary rat hepatocytes. Cycloheximide, a translation elongation inhibitor known to augment intracellular amino acid levels, prevented the effect of bafilomycin on amino acids levels and completely reversed its inhibition of EGF-induced mTORC1 activation. In vivo administration of EGF stimulated the recruitment of Ras homologue enriched in brain (Rheb) but not mammalian target of rapamycin (mTOR) to endosomes and lysosomes. This was inhibited by chloroquine treatment. Our results suggest a role for vacuolar acidification in EGF signaling to mTORC1.