Zhou Ge, Wang Jiping, Zhao Mei, Xie Tong-Xin, Tanaka Noriaki, Sano Daisuke, Patel Ameeta A, Ward Alexandra M, Sandulache Vlad C, Jasser Samar A, Skinner Heath D, Fitzgerald Alison Lea, Osman Abdullah A, Wei Yongkun, Xia Xuefeng, Songyang Zhou, Mills Gordon B, Hung Mien-Chie, Caulin Carlos, Liang Jiyong, Myers Jeffrey N
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Mol Cell. 2014 Jun 19;54(6):960-974. doi: 10.1016/j.molcel.2014.04.024. Epub 2014 May 22.
Many mutant p53 proteins (mutp53s) exert oncogenic gain-of-function (GOF) properties, but the mechanisms mediating these functions remain poorly defined. We show here that GOF mutp53s inhibit AMP-activated protein kinase (AMPK) signaling in head and neck cancer cells. Conversely, downregulation of GOF mutp53s enhances AMPK activation under energy stress, decreasing the activity of the anabolic factors acetyl-CoA carboxylase and ribosomal protein S6 and inhibiting aerobic glycolytic potential and invasive cell growth. Under conditions of energy stress, GOF mutp53s, but not wild-type p53, preferentially bind to the AMPKα subunit and inhibit AMPK activation. Given the importance of AMPK as an energy sensor and tumor suppressor that inhibits anabolic metabolism, our findings reveal that direct inhibition of AMPK activation is an important mechanism through which mutp53s can gain oncogenic function.
许多突变型p53蛋白（mutp53s）具有致癌性的功能获得（GOF）特性，但介导这些功能的机制仍不清楚。我们在此表明，具有GOF的mutp53s在头颈部癌细胞中抑制AMP激活的蛋白激酶（AMPK）信号传导。相反，在能量应激下，下调具有GOF的mutp53s可增强AMPK激活，降低合成代谢因子乙酰辅酶A羧化酶和核糖体蛋白S6的活性，并抑制有氧糖酵解潜能和侵袭性细胞生长。在能量应激条件下，具有GOF的mutp53s而非野生型p53优先结合AMPKα亚基并抑制AMPK激活。鉴于AMPK作为能量传感器和抑制合成代谢的肿瘤抑制因子的重要性，我们的研究结果表明，直接抑制AMPK激活是mutp53s获得致癌功能的重要机制。
