A role of DNA-dependent protein kinase for the activation of AMP-activated protein kinase in response to glucose deprivation

作者：Amatya Parmeshwar Narayan; Kim Hong Beum; Park Seon Joo; Youn Cha Kyung; Hyun Jin Won; Chang In Youb; Lee Jung Hee^*; You Ho Jin

来源：Biochimica et Biophysica Acta-Molecular Cell Research, 2012, 1823(12): 2099-2108.

DOI：10.1016/j.bbamcr.2012.08.022

• DNA-PKcs
• AMPK
• ACC
• Glucose depletion

The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) plays an essential role in double-strand break repair by initially recognizing and binding to DNA breaks. Here, we show that DNA-PKcs interacts with the regulatory gamma 1 subunit of AMP-activated protein kinase (AMPK), a heterotrimeric enzyme that has been proposed to function as a %26quot;fuel gauge%26quot; to monitor changes in the energy status of cells and is controlled by the upstream kinases LKB1 and Ca2+/calmodulin-dependent kinase kinase (CaMKK). In co-immunoprecipitation analyses, DNA-PKcs and AMPK gamma 1 interacted physically in DNA-PKcs-proficient M059K cells but not in DNA-PKcs-deficient M059J cells. Glucose deprivation-stimulated phosphorylation of AMPK alpha on Thr172 and of acetyl-CoA carboxylase (ACC). a downstream target of AMPK, is substantially reduced in M059J cells compared with M059K cells. The inhibition or down-regulation of DNA-PKcs by the DNA-PKcs inhibitors, wortmannin and Nu7441, or by DNA-PKcs siRNA caused a marked reduction in AMPK phosphotylation, AMPK activity, and ACC phosphorylation in response to glucose depletion in M059K, WI38, and IMR90 cells. In addition, DNA-DNA-PKcs(-/-) mouse embryonic fibroblasts (MEFs) exhibited decreased AMPK activation in response to glucose-free conditions. Furthermore, the knockdown of DNA-PKcs led to the suppression of AMPK (Thrl 72) phosphorylation in LKB1-deficient HeLa cells under glucose deprivation. Taken together, these findings support the positive regulation of AMPK activation by DNA-PKcs under glucose-deprived conditions in mammalian cells.

• 出版日期2012-12