Li Yan, Xiong Hua, Yang Da-Qing
The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
Chin J Cancer. 2012 Aug;31(8):364-72. doi: 10.5732/cjc.012.10086. Epub 2012 Jun 26.
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar ataxia and oculocutaneous telangiectasias. The gene mutated in this disease, ATM (A-T, mutated), encodes a 370-kDa Ser/Thr protein kinase. ATM not only mediates cellular response to DNA damage but also acts as an activator of Akt in response to insulin. However, despite intensive studies, the mechanism underlying the neuronal degeneration symptoms of human A-T is still poorly understood. We found that the topoisomerase inhibitors etoposide and camptothecin readily induced apoptosis in undifferentiated proliferating SH-SY5Y cells but could not induce apoptosis in neuronally differentiated SH-SY5Y cells. In addition, etoposide induced p53 phosphorylation and H2AX foci formation in proliferating SH-SY5Y cells but failed to do so in differentiated SH-SY5Y cells. Moreover, while inhibition of ATM in undifferentiated SH-SY5Y cells partially protected them from etoposide-induced apoptosis, the same treatment had no effect on cell viability in differentiated SH-SY5Y cells. These results suggest that DNA damage or defective response to DNA damage is not the cause of neuronal cell death in human A-T. In contrast, we discovered that Akt phosphorylation was inhibited when ATM activity was suppressed in differentiated SH-SY5Y cells. Furthermore, inhibition of ATM induced apoptosis following serum starvation in neuronally differentiated SH-SY5Y cells but could not trigger apoptosis under the same conditions in undifferentiated proliferating SH-SY5Y cells. These results demonstrate that ATM mediates the Akt signaling and promotes cell survival in neuron-like human SH-SY5Y cells, suggesting that impaired activation of Akt is the reason for neuronal degeneration in human A-T.
共济失调毛细血管扩张症（A-T）是一种常染色体隐性疾病，其特征为小脑共济失调和眼皮肤毛细血管扩张。该疾病中发生突变的基因ATM（A-T，突变型）编码一种370 kDa的丝氨酸/苏氨酸蛋白激酶。ATM不仅介导细胞对DNA损伤的反应，还作为对胰岛素反应中Akt的激活剂。然而，尽管进行了深入研究，人类A-T神经元变性症状的潜在机制仍知之甚少。我们发现，拓扑异构酶抑制剂依托泊苷和喜树碱很容易在未分化的增殖性SH-SY5Y细胞中诱导凋亡，但不能在神经元分化的SH-SY5Y细胞中诱导凋亡。此外，依托泊苷在增殖性SH-SY5Y细胞中诱导p53磷酸化和H2AX灶形成，但在分化的SH-SY5Y细胞中未能诱导。而且，虽然在未分化的SH-SY5Y细胞中抑制ATM可部分保护它们免受依托泊苷诱导的凋亡，但相同处理对分化的SH-SY5Y细胞的细胞活力没有影响。这些结果表明，DNA损伤或对DNA损伤的缺陷反应不是人类A-T中神经元细胞死亡的原因。相反，我们发现，在分化的SH-SY5Y细胞中抑制ATM活性时，Akt磷酸化受到抑制。此外，在神经元分化的SH-SY5Y细胞中，抑制ATM会在血清饥饿后诱导凋亡，但在未分化的增殖性SH-SY5Y细胞的相同条件下不能触发凋亡。这些结果表明，ATM介导Akt信号传导并促进类神经元人类SH-SY5Y细胞的存活，这表明Akt激活受损是人类A-T中神经元变性的原因。
