2月14日，內(nèi)蒙古大學(xué)生命科學(xué)學(xué)院候鑫教授領(lǐng)導(dǎo)的科研小組在Oncogene 雜志上發(fā)表了題為“A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation”的論文,，揭示了NUAK1參與LKB1相關(guān)信號(hào)通路,、調(diào)控細(xì)胞生長與增殖的分子機(jī)制。新研究發(fā)現(xiàn)推動(dòng)科研人員更深入地了解了LKB1/NUAK1的抑癌機(jī)理,。
NUAK1又稱AMPK-related protein kinase 5（ARK5）,，是2003年由Suzuki等發(fā)現(xiàn)的AMPK亞家族的成員，該蛋白分子量為74kD,，對(duì)SAMS peptide等具有激酶活性,，其催化結(jié)構(gòu)域的氨基酸序列與NUAK2（又稱SNARK）的同源性為84％。早期的研究證實(shí)NUAK1是一種與細(xì)胞生存和腫瘤細(xì)胞存活有關(guān)的因子,。2004年Lizcano等在研究中發(fā)現(xiàn)AMPK亞家族中的NUAK1,、 NUAK2等12種AMPK相關(guān)激酶（AMPK-related kinase）均為LKB1的底物，可以被LKB1磷酸化而激活,。盡管大量研究數(shù)據(jù)表明NUAK1參與了誘導(dǎo)腫瘤存活,、侵襲和p53非依賴性的細(xì)胞衰老，然而目前對(duì)于其確切的功能及作用機(jī)制仍知之甚少,。
過去的研究證實(shí)p53蛋白p53蛋白Ser15和Ser392的磷酸化依賴于LKB1,，LKB1借此調(diào)控p53的穩(wěn)定性并可導(dǎo)致細(xì)胞周期的G1期阻滯。在新論文中,，研究人員證實(shí)了NUAK1是LKB1信號(hào)通路的重要成員,，并在介導(dǎo)LKB1對(duì)P53的調(diào)控中發(fā)揮著關(guān)鍵性的作用。研究人員在體內(nèi)和體外實(shí)驗(yàn)中發(fā)現(xiàn)存在野生型LKB1的條件下,，NUAK1可直接與p53發(fā)生相互作用，并使其磷酸化,。進(jìn)一步的研究證實(shí)LKB1可通過使NUAK1 Thr211位點(diǎn)磷酸化從而激活NUAK1,，激活的NUAK1進(jìn)而介導(dǎo)p53磷酸化,。此外，研究人員還證實(shí)LKB1/NUAK1 激活后,，NUAK1通過在細(xì)胞核內(nèi)與p53的相互作用,，從而結(jié)合到p21/WAF1啟動(dòng)子p53反應(yīng)元件上，通過誘導(dǎo)p21/WAF1進(jìn)而導(dǎo)致細(xì)胞發(fā)生了G1/S細(xì)胞周期阻滯,。
新研究結(jié)果揭示了NUAK1在LKB1相關(guān)的信號(hào)通路上的新功能,，證明NUAK1可通過與p53的直接互作而參與調(diào)控細(xì)胞增殖，發(fā)揮腫瘤抑制作用,。（生物谷Bioon.com）
生物谷推薦原文出處：
Oncogene doi:10.1038/onc.2011.19
A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation
X Hou, J-E Liu, W Liu, C-Y Liu, Z-Y Liu and Z-Y Sun
It has been suggested that adenosine monophosphate-activated protein kinase (AMPK) and 12 AMPK-related kinases (ARK), including novel (nua) kinase family 1 (NUAK1), are activated by master kinase LKB1, a major tumor suppressor. Apart from evidence to suggest that NUAK1 participates in induction of tumor survival, invasion and p53-independent cellular senescence, its detailed biological functions remain unclear. Here we showed that in the presence of wild-type LKB1, NUAK1 directly interacts with and phosphorylates p53 in vitro and in vivo. The phosphorylation of p53 induced by LKB1 required the kinase activity of NUAK1 and phosphorylation of NUAK1 at Thr211 by LKB1 was essential for its kinase activity, which leads to the conclusion that LKB1 activates NUAK1 and regulates phosphorylation of p53 through the NUAK1 kinase, at least partially. LKB1/NUAK1 activation leads to cell cycle arrest at the G1/S border by inducing expression of p21/WAF1. Under the regulation of LKB1, NUAK1 interacts with p53 in the nucleus and binds to the p53-responsive element of p21/WAF1 promoter. These findings have highlighted a novel role for NUAK1 in LKB1-related signaling pathways; NUAK1 can regulate cell proliferation and exert tumor suppression through direct interaction with p53.
