近日，臺(tái)灣大學(xué)（臺(tái)大）與美國(guó)約翰霍普金斯醫(yī)學(xué)院合作,，證實(shí)有2種蛋白質(zhì)可調(diào)控AMPK（俗稱長(zhǎng)壽基因），這一發(fā)現(xiàn)2月14日刊登于國(guó)際頂尖生物醫(yī)學(xué)期刊《自然》（Nature）,。報(bào)道指出,，此次發(fā)現(xiàn)意義重大，除揭開了部分老化謎團(tuán),，還為開發(fā)癌癥新藥帶來曙光,。
該研究第一作者林育誼說，過去世界學(xué)術(shù)界僅知人體內(nèi)有2大類共數(shù)10種蛋白質(zhì)與細(xì)胞老化相關(guān),，一類是“乙?；D(zhuǎn)移酶”,，另一類是“去乙酰酶”，人年輕時(shí),，2類蛋白質(zhì)維持能量均衡,，當(dāng)年紀(jì)漸大，去乙酰酶較活化,，使能量不均,，進(jìn)而罹患與老化有關(guān)病癥如癌癥、高血壓等,。
林育誼說,，要治療上述疾病，需要先弄清這2大類蛋白質(zhì)與其它基因的交互作用,，他與成員透過改良的脫氧核糖核酸干擾技術(shù),，對(duì)已知與老化相關(guān)的AMPK基因做交互作用篩檢，才發(fā)現(xiàn)有2種蛋白質(zhì)：HDAC1,、p300與AMPK相關(guān),。
林育誼表示，當(dāng)HDAC1活化,，AMPK會(huì)受抑制,，p300則有相反作用。這是學(xué)術(shù)界首次找到可調(diào)控AMPK的蛋白質(zhì),，對(duì)解開使人老化的“去乙?；?rdquo;原因踏出一大步。
林育誼形容脫氧核糖核酸干擾技術(shù)像facebook,，通過facebook就可知某人有哪些朋友,，及其彼此的關(guān)系，而運(yùn)用該技術(shù)就能分辨出這些蛋白質(zhì)間的關(guān)系,，知道其相互作用如何,。
呂金盈指與老化相關(guān)基因很多，臺(tái)大無法據(jù)新技術(shù)研發(fā)長(zhǎng)壽藥,，但團(tuán)隊(duì)目前正在對(duì)肝癌,、腸癌、甲狀腺癌等抗癌藥物進(jìn)行分析,，以利研發(fā)與老化有關(guān)的癌癥治療藥物,。
據(jù)了解，約翰霍普金斯大學(xué)醫(yī)學(xué)院享有盛名,，在美國(guó)排名僅次于哈佛大學(xué)醫(yī)學(xué)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.
