Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland.
PLoS One. 2011;6(9):e21486. doi: 10.1371/journal.pone.0021486. Epub 2011 Sep 22.
Translational control is utilized as a means of regulating gene expression in many species. In most cases, posttranscriptional regulatory mechanisms play an important role in stress response pathways and can lead to dysfunctional physiology if blocked by mutations. Carnitine Palmitoyltransferase 1 C (CPT1C), the brain-specific member of the CPT 1 family, has previously been shown to be involved in regulating metabolism in situations of energy surplus.
Sequence analysis of the CPT1C mRNA revealed that it contains an upstream open reading frame (uORF) in the 5' UTR of its mRNA. Using CPT1C 5' UTR/luciferase constructs, we investigated the role of the uORF in translational regulation. The results presented here show that translation from the CPT1C main open reading frame (mORF) is repressed by the presence of the uORF, that this repression is relieved in response to specific stress stimuli, namely glucose deprivation and palmitate-BSA treatment, and that AMPK inhibition can relieve this uORF-dependent repression.
The fact that the mORF regulation is relieved in response to a specific set of stress stimuli rather than general stress response, hints at an involvement of CPT1C in cellular energy-sensing pathways and provides further evidence for a role of CPT1C in hypothalamic regulation of energy homeostasis.
在许多物种中，翻译控制被用作调节基因表达的一种手段。在大多数情况下，转录后调控机制在应激反应途径中起着重要作用，如果被突变阻断，可能导致生理功能障碍。肉碱棕榈酰转移酶 1C（CPT1C）是 CPT1 家族中脑特异性成员，先前已被证明参与调节能量过剩情况下的代谢。
CPT1C mRNA 的序列分析表明，其 mRNA 的 5'UTR 中存在一个上游开放阅读框（uORF）。我们使用 CPT1C 5'UTR/荧光素酶构建体研究了 uORF 在翻译调控中的作用。这里呈现的结果表明，uORF 的存在抑制了 CPT1C 主开放阅读框（mORF）的翻译，这种抑制在受到特定应激刺激时得到缓解，即葡萄糖剥夺和棕榈酸-BSA 处理，而 AMPK 抑制可以缓解这种依赖 uORF 的抑制。
mORF 调节仅在响应特定的应激刺激而不是一般应激反应时得到缓解，这表明 CPT1C 参与细胞能量感应途径，并为 CPT1C 在下丘脑对能量稳态的调节中的作用提供了进一步的证据。
