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Mimic Phosphorylation of SET at Ser 9 Inhibits PP2A Activity

Author: YanTongHai
Tutor: WangXiaoChuan
School: Huazhong University of Science and Technology
Course: Pathology and Pathophysiology
Keywords: Alzheimer’s Disease SET/I2PP2A PP2A Tau Phosphorylation Apoptosis
CLC: R749.16
Type: Master's thesis
Year: 2011
Downloads: 42
Quote: 0
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Abstract


Background: The nuclear protein SET/I2PP2A is an endogenous inhibitor of the serine/threonine phosphatase PP2A, which deficiency in cytoplasma acts as a key impetus on Alzheimer’s Disease (AD) onset. Currently, it is still not clear how SET/I2PP2A transports from nuclear to cytoplasma and subsequently influences PP2A activity. The present study firstly investigated and compared the difference between phosphorylated SET and non-phosphorylated SET/I2PP2A on PP2A activity.Methods: We carried out site-directed mutagenesis to mutate Ser-9 of SET to either alanine (S9A) or glutamic acid (S9E), mimicing respectively the non-phosphorylated (npSET) or phosphorylated (pSET) form of SET. HEK293/tau cells were cultured and transfected with pcDNA3.1, wild type SET (wtSET), npSET, pSET respectively. Cell viability was detected by CCK-8 technique 24, 48, 72 hours after transfection. Tau phosphorylation and the related enzymes’activity were assayed by Western blot, immunoflurescence and commercial kit respectively.Results: (1) 24 hours post-transfection, phosphorylated SET could decrease cell viability, while wild type SET did it 48 hours after transfection and non-phosphorylated SET didn’t alter cell viability at the three time points.(2) Meanwhile, PP2A activities in either pSET or wtSET treated HEK293/tau cells were significantly decreased as compared with that of pcDNA3.1 control group, but npSET didn’t influence PP2A activity. Interestingly, when directly comparing between pSET and wtSET, we also found that pSET inhibited PP2A activity more efficiently than wtSET by 25.2% (p=0.006).(3) In accordance with the decrease of PP2A, tau phosphorylation at Ser396, Ser262, Thr205, Ser214, Ser404 and Ser199 was marked increased 48 hours after either pSET or wt SET transfection, but npSET did not.(4) 48 hours post-transfection, pSET upregulated phosphorylates p53 through p38 MAPK as well as the ratio of bax/bcl-2. The cell apoptosis was not observed.(5) Overexpression of wtSET, npSET and pSET upregulate the activity of GSK-3β.(6) npSET and pSET increase PP2A phosphorylation at Y307.(7) wtSET and pSET significantly increase PP2A demethylation at Leu 309.(8) Phosphorylation of SET at Ser 9 activates Akt and simultaneous inhibits Akt exacerbates the p53-mediated apoptosis.Conclusion:(1) Phosphorylation of SET at Ser 9 significantly promotes an inhibition of PP2A.(2) Modification of SET phosphorylation does not influence the upregulation of GSK-3βactivity.(3) Phosphorylation of SET at Ser 9 againsts the occurance of apoptosis.

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CLC: > Medicine, health > Neurology and psychiatry > Psychiatry > Cerebral organic mental disorder > Elderly as early as possible the old disorder
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