Knockdown of akt1 promotes Akt2 upregulation and resistance to oxidative-stress-induced apoptosis through control of multiple signaling pathways

Lan Zhang, Shuming Sun, Jie Zhou, Jiao Liu, Jia Han Lv, Xiang Qiang Yu, Chi Li, Lili Gong, Qin Yan, Mi Deng, Ling Xiao, Haili Ma, Jin Ping Liu, Yun Lei Peng, Dao Wang, Gao Peng Liao, Li Jun Zou, Wen Bin Liu, Ya Mei Xiao, David Wan Cheng Li

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

The Akt signaling pathway plays a key role in promoting the survival of various types of cells from stress-induced apoptosis, and different members of the Akt family display distinct physiological roles. Previous studies have shown that in response to UV irradiation, Akt2 is sensitized to counteract the induced apoptosis. However, in response to oxidative stress such as hydrogen peroxide, it remains to be elucidated what member of the Akt family would be activated to initiate the signaling cascades leading to resistance of the induced apoptosis. In the present study, we present the first evidence that knockdown of Akt1 enhances cell survival under exposure to 50μM H 2O2. This survival is derived from selective upregulation and activation of Akt2 but not Akt3, which initiates 3 major signaling cascades. First, murine double minute 2 (MDM2) is hyperphosphorylated, which promotes p53 degradation and attenuates its Ser-15 phosphorylation, significantly attenuating Bcl-2 homologous antagonist killer (Bak) upregulation. Second, Akt2 activation inactivates glycogen synthase kinase 3 beta (GSK-3β) to promote stability of myeloid leukemia cell differentiation protein 1 (MCL-1). Finally, Akt2 activation promotes phosphorylation of FOXO3A toward cytosolic export and thus downregulates Bim expression. Overexpression of Bim enhances H 2O2-induced apoptosis. Together, our results demonstrate that among the Akt family members, Akt2 is an essential kinase in counteracting oxidative-stress-induced apoptosis through multiple signaling pathways.

Original languageEnglish (US)
Pages (from-to)1-17
Number of pages17
JournalAntioxidants and Redox Signaling
Volume15
Issue number1
DOIs
StatePublished - Jul 1 2011

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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  • Cite this

    Zhang, L., Sun, S., Zhou, J., Liu, J., Lv, J. H., Yu, X. Q., Li, C., Gong, L., Yan, Q., Deng, M., Xiao, L., Ma, H., Liu, J. P., Peng, Y. L., Wang, D., Liao, G. P., Zou, L. J., Liu, W. B., Xiao, Y. M., & Li, D. W. C. (2011). Knockdown of akt1 promotes Akt2 upregulation and resistance to oxidative-stress-induced apoptosis through control of multiple signaling pathways. Antioxidants and Redox Signaling, 15(1), 1-17. https://doi.org/10.1089/ars.2010.3560