2月14日，内蒙古大学生命科学学院候鑫教授领导的科研小组在Oncogene 杂志上发表了题为“A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation”的论文，揭示了NUAK1参与LKB1相关信号通路、调控细胞生长与增殖的分子机制。新研究发现推动科研人员更深入地了解了LKB1/NUAK1的抑癌机理。
NUAK1又称AMPK-related protein kinase 5（ARK5），是2003年由Suzuki等发现的AMPK亚家族的成员，该蛋白分子量为74kD，对SAMS peptide等具有激酶活性，其催化结构域的氨基酸序列与NUAK2（又称SNARK）的同源性为84％。早期的研究证实NUAK1是一种与细胞生存和肿瘤细胞存活有关的因子。2004年Lizcano等在研究中发现AMPK亚家族中的NUAK1、 NUAK2等12种AMPK相关激酶（AMPK-related kinase）均为LKB1的底物，可以被LKB1磷酸化而激活。尽管大量研究数据表明NUAK1参与了诱导肿瘤存活、侵袭和p53非依赖性的细胞衰老，然而目前对于其确切的功能及作用机制仍知之甚少。
过去的研究证实p53蛋白p53蛋白Ser15和Ser392的磷酸化依赖于LKB1，LKB1借此调控p53的稳定性并可导致细胞周期的G1期阻滞。在新论文中，研究人员证实了NUAK1是LKB1信号通路的重要成员，并在介导LKB1对P53的调控中发挥着关键性的作用。研究人员在体内和体外实验中发现存在野生型LKB1的条件下，NUAK1可直接与p53发生相互作用，并使其磷酸化。进一步的研究证实LKB1可通过使NUAK1 Thr211位点磷酸化从而激活NUAK1，激活的NUAK1进而介导p53磷酸化。此外，研究人员还证实LKB1/NUAK1 激活后，NUAK1通过在细胞核内与p53的相互作用，从而结合到p21/WAF1启动子p53反应元件上，通过诱导p21/WAF1进而导致细胞发生了G1/S细胞周期阻滞。
新研究结果揭示了NUAK1在LKB1相关的信号通路上的新功能，证明NUAK1可通过与p53的直接互作而参与调控细胞增殖，发挥肿瘤抑制作用。（生物谷Bioon.com）
生物谷推荐原文出处：
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.
