近日，台湾大学（台大）与美国约翰霍普金斯医学院合作，证实有2种蛋白质可调控AMPK（俗称长寿基因），这一发现2月14日刊登于国际顶尖生物医学期刊《自然》（Nature）。报道指出，此次发现意义重大，除揭开了部分老化谜团，还为开发癌症新药带来曙光。
该研究第一作者林育谊说，过去世界学术界仅知人体内有2大类共数10种蛋白质与细胞老化相关，一类是“乙酰基转移酶”，另一类是“去乙酰酶”，人年轻时，2类蛋白质维持能量均衡，当年纪渐大，去乙酰酶较活化，使能量不均，进而罹患与老化有关病症如癌症、高血压等。
林育谊说，要治疗上述疾病，需要先弄清这2大类蛋白质与其它基因的交互作用，他与成员透过改良的脱氧核糖核酸干扰技术，对已知与老化相关的AMPK基因做交互作用筛检，才发现有2种蛋白质：HDAC1、p300与AMPK相关。
林育谊表示，当HDAC1活化，AMPK会受抑制，p300则有相反作用。这是学术界首次找到可调控AMPK的蛋白质，对解开使人老化的“去乙酰化”原因踏出一大步。
林育谊形容脱氧核糖核酸干扰技术像facebook，通过facebook就可知某人有哪些朋友，及其彼此的关系，而运用该技术就能分辨出这些蛋白质间的关系，知道其相互作用如何。
吕金盈指与老化相关基因很多，台大无法据新技术研发长寿药，但团队目前正在对肝癌、肠癌、甲状腺癌等抗癌药物进行分析，以利研发与老化有关的癌症治疗药物。
据了解，约翰霍普金斯大学医学院享有盛名，在美国排名仅次于哈佛大学医学院。（生物谷Bioon.com）
doi:10.1038/nature10804
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Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK
Yu-yi Lin, Samara Kiihl, Yasir Suhai, Shang-Yun Liu, Yi-hsuan Chou, Zheng Kuang, Jin-ying Lu, Chin Ni Khor, Chi-Long Lin, Joel S. Bader,Rafael Irizarry & Jef D. Boeke
First identified as histone-modifying proteins, lysine acetyltransferases (KATs) and deacetylases (KDACs) antagonize each other through modification of the side chains of lysine residues in histone proteins1. Acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms2, 3, 4, 5, 6, but the corresponding enzymes and substrate-specific functions of the modifications are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs7 remain enigmatic, and the substrate spectra of each KDAC lack comprehensive definition. Here we dissect the functional specificity of 12 critical human KDACs using a genome-wide synthetic lethality screen8, 9, 10, 11, 12, 13 in cultured human cells. The genetic interaction profiles revealed enzyme–substrate relationships between individual KDACs and many important substrates governing a wide array of biological processes including metabolism, development and cell cycle progression. We further confirmed that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 and p300. Deacetylation of AMPK enhances physical interaction with the upstream kinase LKB1, leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. These findings provide new insights into previously underappreciated metabolic regulatory roles of HDAC1 in coordinating nutrient availability and cellular responses upstream of AMPK, and demonstrate the importance of high-throughput genetic interaction profiling to elucidate functional specificity and critical substrates of individual human KDACs potentially valuable for therapeutic applications.
