doi: 10.5732/cjc.012.10086

Functional switching of ATM: sensor of DNA damage in proliferating cells and mediator of Akt survival signal in post-mitotic human neuron-like cells

Yan Li, Hua Xiong, Da-Qing Yang

The Hormel Institute, University of Minnesota, Austin, MN 55912, USA

[Abstract] 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.

Chinese Journal of Cancer 2012, Volume: 31, Issue 8, Page: 364-372

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Yan Li, Hua Xiong, Da-Qing Yang. Functional switching of ATM: sensor of DNA damage in proliferating cells and mediator of Akt survival signal in post-mitotic human neuron-like cells. Chin J Cancer. 2012, 31(8):364-372. doi:10.5732/cjc.012.10086


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