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Functional antagonism between p53 and WWOX in vivo leads to protein aggregation in the brain
Author(s) -
Chang Nan-Shan,
Chou Pei-Yi,
Lin Sing-Ru,
Lee MIng-Hui,
Schultz Lori,
Sze Chun-I
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02745
Subject(s) - wwox , neurodegeneration , cancer research , suppressor , downregulation and upregulation , cancer , neuroscience , tumor progression , chemistry , microbiology and biotechnology , biology , medicine , disease , biochemistry , gene
Tumor suppressor WW domain‐containing oxidoreductase WWOX is a newly defined risk factor for Alzheimer’s disease (AD) in 2019. We discovered WWOX in 2000 and have been working on how WWOX blocks AD progression since then. We reported that WWOX starts to downregulate in the brain cortex and hippocampus in the middle‐aged normal individuals. Consequently, a likely scenario of slow activation of a protein aggregation cascade occurs with age as shown in the normal and AD brains as follows: 1) TRAPPC6AΔ, TIAF1 and SH3GLB2 aggregation, 2) caspase activation and APP degradation, and 3) final aggregation of amyloid β and Tau. The protein aggregation event may last 20 to 30 years and even longer. Here, we identified a tumor suppressor WWOX/TIAF1/p53 triad, which is potent in cancer suppression by blocking cancer cell migration, anchorage‐independent growth and SMAD promoter activation, and causing apoptosis. Yet, when p53 functionally antagonizes with WWOX in the mouse brain, p53 blocks WWOX‐mediated inhibition of inflammatory immune response induced by cancer, and this leads to protein aggregation in the brain as seen in AD and other neurodegeneration. The aggregated proteins include APP, amyloid β, neurofibrillary tangles (or tangled tau), p‐ERK and α‐tubulin. Together, we have discovered for the first time that WWOX limitation of neurodegeneration is blocked by p53 under inflammatory conditions in vivo . Support or Funding Information Ministry of Science and Technology, Taiwan, Department of Defense, USA, and National Health Research Institutes, Taiwan.Summary illustration. Three scenarios account for cancer growth or suppression: 1) loss of WWOX, p53 and TIAF1 increases cancer growth and metastasis; 2) stabilized p53/WWOX/TIAF1 triad suppresses cancer growth, inhibits metastasis, and induces apoptosis; 3) functional antagonism between p53 and WWOX allows cancer cell growth and yet induces inflammation for causing neural protein aggregation as seen in the Alzheimer’s disease.