Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Mol Cell. 2010 Dec 10;40(5):823-33. doi: 10.1016/j.molcel.2010.11.035.
The BH3-only protein, Noxa, is induced in response to apoptotic stimuli, such as DNA damage, hypoxia, and proteasome inhibition in most human cells. Noxa is constitutively expressed in proliferating cells of hematopoietic lineage and required for apoptosis in response to glucose stress. We show that Noxa is phosphorylated on a serine residue (S(13)) in the presence of glucose. Phosphorylation promotes its cytosolic sequestration and suppresses its apoptotic function. We identify Cdk5 as the Noxa kinase and show that Cdk5 knockdown or expression of a Noxa S(13) to A mutant increases sensitivity to glucose starvation, confirming that the phosphorylation is protective. Both glucose deprivation and Cdk5 inhibition promote apoptosis by dephosphorylating Noxa. Paradoxically, Noxa stimulates glucose consumption and may enhance glucose turnover via the pentose phosphate pathway rather than through glycolysis. We propose that Noxa plays both growth-promoting and proapoptotic roles in hematopoietic cancers with phospho-S(13) as the glucose-sensitive toggle switch controlling these opposing functions.
BH3 仅蛋白 Noxa 可响应凋亡刺激物（如 DNA 损伤、缺氧和蛋白酶体抑制）在大多数人类细胞中诱导产生。Noxa 在造血谱系的增殖细胞中持续表达，并且在响应葡萄糖应激时需要凋亡。我们表明，在葡萄糖存在的情况下，Noxa 在丝氨酸残基 (S(13)) 上发生磷酸化。磷酸化促进其细胞质隔离并抑制其凋亡功能。我们鉴定出 Cdk5 是 Noxa 的激酶，并表明 Cdk5 敲低或表达 Noxa S(13) 到 A 突变体增加了对葡萄糖饥饿的敏感性，这证实了磷酸化是具有保护作用的。葡萄糖剥夺和 Cdk5 抑制均通过去磷酸化 Noxa 来促进细胞凋亡。矛盾的是，Noxa 通过戊糖磷酸途径（而不是通过糖酵解）刺激葡萄糖消耗并可能增强葡萄糖周转率。我们提出，Noxa 在具有磷酸化 S(13) 的造血性癌症中发挥促进生长和促凋亡作用，作为控制这些相反功能的葡萄糖敏感转换开关。
