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      A p53/TIAF1/WWOX triad exerts cancer suppression but may cause brain protein aggregation due to p53/WWOX functional antagonism

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          Abstract

          Background

          Tumor suppressor WWOX physically binds p53 and TIAF1 and together induces apoptosis and tumor suppression. To understand the molecular action, here we investigated the formation of WWOX/TIAF1/p53 triad and its regulation of cancer cell migration, anchorage-independent growth, SMAD promoter activation, apoptosis, and potential role in neurodegeneration.

          Methods

          Time-lapse microscopy was used to measure the extent of cell migration. Protein/protein interactions were determined by co-immunoprecipitation, FRET microscopy, and yeast two-hybrid analysis. The WWOX/TIAF1/p53 triad-mediated cancer suppression was determined by measuring the extent of cell migration, anchorage-independent growth, SMAD promoter activation, and apoptosis. p53-deficient lung cancer cell growth in nude mice was carried out to assess the tumor suppressor function of ectopic p53 and/or WWOX.

          Results

          Wwox-deficient MEF cells exhibited constitutive Smad3 and p38 activation and migrated individually and much faster than wild type cells. TGF-β increased the migration of wild type MEF cells, but significantly suppressed Wwox knockout cell migration. While each of the triad proteins is responsive to TGF-β stimulation, ectopically expressed triad proteins suppressed cancer cell migration, anchorage-independent growth, and SMAD promoter activation, as well as caused apoptosis. The effects are due in part to TIAF1 polymerization and its retention of p53 and WWOX in the cytoplasm. p53 and TIAF1 were effective in suppressing anchorage-independent growth, and WWOX ineffective. p53 and TIAF1 blocked WWOX or Smad4-regulated SMAD promoter activation. WWOX suppressed lung cancer NCI-H1299 growth and inhibited splenomegaly by inflammatory immune response, and p53 blocked the event in nude mice. The p53/WWOX-cancer mice exhibited BACE upregulation, APP degradation, tau tangle formation, and amyloid β generation in the brain and lung.

          Conclusion

          The WWOX/TIAF1/p53 triad is potent in cancer suppression by blocking cancer cell migration, anchorage-independent growth and SMAD promoter activation, and causing apoptosis. Yet, p53 may functionally antagonize with WWOX. p53 blocks WWOX inhibition of inflammatory immune response induced by cancer, and this leads to protein aggregation in the brain as seen in the Alzheimer’s disease and other neurodegeneration.

          Electronic supplementary material

          The online version of this article (10.1186/s12964-019-0382-y) contains supplementary material, which is available to authorized users.

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          Most cited references45

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          p53 and its mutants in tumor cell migration and invasion

          In about half of all human cancers, the tumor suppressor p53 protein is either lost or mutated, frequently resulting in the expression of a transcriptionally inactive mutant p53 protein. Loss of p53 function is well known to influence cell cycle checkpoint controls and apoptosis. But it is now clear that p53 regulates other key stages of metastatic progression, such as cell migration and invasion. Moreover, recent data suggests that expression of mutant p53 is not the equivalent of p53 loss, and that mutant p53s can acquire new functions to drive cell migration, invasion, and metastasis, in part by interfering with p63 function.
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            WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer.

            Studies were conducted with the final goal of identifying genes of interest mapping to the chromosome region 16q23.3-24.1, an area commonly affected by allelic losses in breast cancer. To this end we generated a detailed physical map of the genomic region spanning between sequence-tagged site markers D16S518 and D16S516. To identify candidate genes, we used shotgun genomic sequencing as well as isolation and analysis of transcripts mapping to the area of interest. We identified and cloned a novel gene, the genomic structure of which spans the whole region of interest. We named this gene WWOX because it contains two WW domains coupled to a region with high homology to the short-chain dehydrogenase/reductase family of enzymes. The ORF of WWOX is 1245 bp long, encoding a 414-amino acid protein. This gene is composed of nine exons. We performed a mutation screening of WWOX exons in a panel of breast cancer lines, most of which are hemizygous for the 16q genomic region indicated. We found no evidence of mutations, thus indicating that WWOX is probably not a tumor suppressor gene. However, we observed that one case of homozygous deletion as well as two previously described translocation breakpoints map to intronic regions of this gene. We speculate that WWOX may span the yet uncharacterized common fragile site FRA16D region. In expression studies we found overexpression of WWOX in breast cancer cell lines when compared with normal breast cells and tissues. The highest normal expression of WWOX was observed in hormonally regulated tissues such as testis, ovary, and prostate. This expression pattern and the presence of a short-chain dehydrogenase/reductase domain and specific amino acid features suggest a role for WWOX in steroid metabolism. Interestingly, the presence of WW domains in the structure of WWOX indicate the likelihood that this protein physically interacts with other proteins. The unique features of WWOX and its possible association with cancer processes make it an interesting target for further investigation.
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              Hyaluronidase induction of a WW domain-containing oxidoreductase that enhances tumor necrosis factor cytotoxicity.

              To determine how hyaluronidase increases certain cancer cell sensitivity to tumor necrosis factor (TNF) cytotoxicity, we report here the isolation and characterization of a hyaluronidase-induced murine WW domain-containing oxidoreductase (WOX1). WOX1 is composed of two N-terminal WW domains, a nuclear localization sequence, and a C-terminal alcohol dehydrogenase (ADH) domain. WOX1 is mainly located in the mitochondria, and the mitochondrial targeting sequence was mapped within the ADH domain. Induction of mitochondrial permeability transition by TNF, staurosporine, and atractyloside resulted in WOX1 release from mitochondria and subsequent nuclear translocation. TNF-mediated WOX1 nuclear translocation occurred shortly after that of nuclear factor-kappaB nuclear translocation, whereas both were independent events. WOX1 enhanced TNF cytotoxicity in L929 cells via its WW and ADH domains as determined using stable cell transfectants. In parallel with this observation, WOX1 also enhanced TRADD (TNF receptor-associated death domain protein)-mediated cell death in transient expression experiments. Antisense expression of WOX1 raised TNF resistance in L929 cells. Enhancement of TNF cytotoxicity by WOX1 is due, in part, to its significant down-regulation of the apoptosis inhibitors Bcl-2 and Bcl-x(L) (>85%), but up-regulation of pro-apoptotic p53 ( approximately 200%) by the ADH domain. When overexpressed, the ADH domain mediated apoptosis, probably due to modulation of expression of these proteins. The WW domains failed to modulate the expression of these proteins, but sensitized COS-7 cells to TNF killing and mediated apoptosis in various cancer cells independently of caspases. Transient cotransfection of cells with both p53 and WOX1 induced apoptosis in a synergistic manner. WOX1 colocalizes with p53 in the cytosol and binds to the proline-rich region of p53 via its WW domains. Blocking of WOX1 expression by antisense mRNA abolished p53 apoptosis. Thus, WOX1 is a mitochondrial apoptogenic protein and an essential partner of p53 in cell death.
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                Author and article information

                Contributors
                tomatoanny@gmail.com
                ninthin@yahoo.com.tw
                estilee@gmail.com
                lrschultz@npacc.net
                chuni.sze@gmail.com
                changns@mail.ncku.edu.tw
                Journal
                Cell Commun Signal
                Cell Commun. Signal
                Cell Communication and Signaling : CCS
                BioMed Central (London )
                1478-811X
                17 July 2019
                17 July 2019
                2019
                : 17
                Affiliations
                [1 ]ISNI 0000 0004 0532 3255, GRID grid.64523.36, Institute of Molecular Medicine, National Cheng Kung University, College of Medicine, ; Tainan, Taiwan 70101 Republic of China
                [2 ]ISNI 0000 0004 0462 9834, GRID grid.420546.1, Laboratory of Molecular Immunology, Guthrie Research Institute, ; Sayre, PA 18840 USA
                [3 ]ISNI 0000 0004 0532 3255, GRID grid.64523.36, Department of Cell Biology and Anatomy, , National Cheng Kung University, College of Medicine, ; Tainan, Taiwan 70101 Republic of China
                [4 ]ISNI 0000 0000 9813 9625, GRID grid.420001.7, Department of Neurochemistry, , New York State Institute for Basic Research in Developmental Disabilities, ; Staten Island, NY 10314 USA
                [5 ]ISNI 0000 0001 0083 6092, GRID grid.254145.3, Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, ; Taichung, 40402 Taiwan, Republic of China
                Article
                382
                10.1186/s12964-019-0382-y
                6637503
                31315632
                f8a542e0-4e91-4a9b-b0f5-1d1825838cea
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: 107-2320-B-006 -058 -MY3
                Award ID: 107-2320-B-006-005
                Award Recipient :
                Funded by: National Health Research Institutes Taiwan
                Award ID: NHRI-EX107-10734NI
                Award Recipient :
                Funded by: Ministry of Science and Technology Taiwan
                Award ID: 106-2320-B-006-061
                Award ID: 106-2320-B-006-017
                Award ID: 105-2320-B-006-036
                Award Recipient :
                Funded by: Ministry of Science and Technology Taiwan
                Award ID: 105-2320-B-006-046
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Cell biology
                tumor suppressor,wwox,p53,tiaf1,cell migration,promoter activation
                Cell biology
                tumor suppressor, wwox, p53, tiaf1, cell migration, promoter activation

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