title: Knockdown of Akt1 promotes Akt2 upregulation and resistance to oxidative-stress-induced apoptosis through control of multiple signaling pathways.
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 50 μM H(2)O(2). 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(2)O(2)-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.
authors.affiliation: University of Nebraska Medical Center, Omaha, 68198-5870, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.forename: Shuming
authors.initials: S
authors.lastname: Sun
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Jiao
authors.initials: J
authors.lastname: Liu
authors.forename: Jia-Han
authors.initials: JH
authors.lastname: Lv
authors.forename: Xiang-Qiang
authors.initials: XQ
authors.lastname: Yu
authors.forename: Chi
authors.initials: C
authors.lastname: Li
authors.forename: Lili
authors.initials: L
authors.lastname: Gong
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
authors.forename: Mi
authors.initials: M
authors.lastname: Deng
authors.forename: Ling
authors.initials: L
authors.lastname: Xiao
authors.forename: Haili
authors.initials: H
authors.lastname: Ma
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Liu
authors.forename: Yun-Lei
authors.initials: YL
authors.lastname: Peng
authors.forename: Dao
authors.initials: D
authors.lastname: Wang
authors.forename: Gao-Peng
authors.initials: GP
authors.lastname: Liao
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Zou
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Liu
authors.forename: Ya-Mei
authors.initials: YM
authors.lastname: Xiao
authors.forename: David Wan-Cheng
authors.initials: DW
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D011247:Pregnancy; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C100852:MLF1 protein, human; D011506:Proteins; D051736:Proto-Oncogene Proteins c-mdm2; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3