I(2)(PP2A) regulates p53 and Akt correlatively and leads the neurons to abort apoptosis.
A chronic neuron loss is the cardinal pathology in Alzheimer disease (AD), but it is still not understood why most neurons in AD brain do not accomplish apoptosis even though they are actually exposed to an environment with enriched proapoptotic factors. Protein phosphatase-2A inhibitor-2 (I(2)(PP2A)), an endogenous PP2A inhibitor, is significantly increased in AD brain, but the role of I(2)(PP2A) in AD-like neuron loss is elusive. Here, we show that I(2)(PP2A) regulates p53 and Akt correlatively. The mechanisms involve activated transcription and p38 MAPK activities. More importantly, we demonstrate that the simultaneous activation of Akt induced by I(2)(PP2A) counteracts the hyperactivated p53-induced cell apoptosis. Furthermore, I(2)(PP2A), p53 and Akt are all elevated in the brain of mouse model and AD patients. Our results suggest that the increased I(2)(PP2A) may trigger apoptosis by p53 upregulation, but due to simultaneous activation of Akt, the neurons are aborted from the apoptotic pathway. This finding contributes to the understanding of why most neurons in AD brain do not undergo apoptosis.
Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
Gong-Ping
GP
Liu
Wei
W
Wei
Xin
X
Zhou
Yao
Y
Zhang
Hai-Hong
HH
Shi
Jun
J
Yin
Xiu-Qing
XQ
Yao
Cai-Xia
CX
Peng
Juan
J
Hu
Qun
Q
Wang
Hong-Lian
HL
Li
Jian-Zhi
JZ
Wang
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D056488:Histone Chaperones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C513473:SET protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt