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 references 45

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p53 and its mutants in tumor cell migration and invasion

Patricia A J Muller, Karen H. Vousden, Jim C. Norman (2011)

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.

Edward K. Hawkins, K J Laflin, C Marcelo Aldaz … (2000)

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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p53 Isoforms: Key Regulators of the Cell Fate Decision.

Sébastien M Joruiz, Jean-Christophe Bourdon (2016)

It is poorly understood how a single protein, p53, can be responsive to so many stress signals and orchestrates very diverse cell responses to maintain/restore cell/tissue functions. The uncovering that TP53 gene physiologically expresses, in a tissue-dependent manner, several p53 splice variants (isoforms) provides an explanation to its pleiotropic biological activities. Here, we summarize a decade of research on p53 isoforms. The clinical studies and the diverse cellular and animal models of p53 isoforms (zebrafish, Drosophila, and mouse) lead us to realize that a p53-mediated cell response is, in fact, the sum of the intrinsic activities of the coexpressed p53 isoforms and that unbalancing expression of different p53 isoforms leads to cancer, premature aging, (neuro)degenerative diseases, inflammation, embryo malformations, or defects in tissue regeneration. Cracking the p53 isoforms' code is, thus, a necessary step to improve cancer treatment. It also opens new exciting perspectives in tissue regeneration.

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Author and article information

Contributors

Pei-Yi Chou: tomatoanny@gmail.com

Sing-Ru Lin: ninthin@yahoo.com.tw

Ming-Hui Lee: estilee@gmail.com

Lori Schultz: lrschultz@npacc.net

Chun-I Sze: chuni.sze@gmail.com

Nan-Shan Chang:

ORCID: http://orcid.org/0000-0002-6889-8756

changns@mail.ncku.edu.tw

Journal

Journal ID (nlm-ta): Cell Commun Signal

Journal ID (iso-abbrev): Cell Commun. Signal

Title: Cell Communication and Signaling : CCS

Publisher: BioMed Central (London )

ISSN (Electronic): 1478-811X

Publication date (Electronic): 17 July 2019

Publication date PMC-release: 17 July 2019

Publication date Collection: 2019

Volume: 17

Electronic Location Identifier: 76

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

Author information

Nan-Shan Chang http://orcid.org/0000-0002-6889-8756

Article

Publisher ID: 382

DOI: 10.1186/s12964-019-0382-y

PMC ID: 6637503

PubMed ID: 31315632

SO-VID: f8a542e0-4e91-4a9b-b0f5-1d1825838cea

License:

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.

History

Date received : 8 February 2019

Date accepted : 4 June 2019

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 : Nan-Shan Chang

Funded by: National Health Research Institutes Taiwan

Award ID: NHRI-EX107-10734NI

Award Recipient : Nan-Shan Chang

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 : Nan-Shan Chang

Funded by: Ministry of Science and Technology Taiwan

Award ID: 105-2320-B-006-046

Award Recipient : Nan-Shan Chang

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ScienceOpen disciplines: Cell biology

Keywords: tumor suppressor,wwox,p53,tiaf1,cell migration,promoter activation

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ScienceOpen disciplines: Cell biology

Keywords: tumor suppressor, wwox, p53, tiaf1, cell migration, promoter activation

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

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Most cited references 45

p53 and its mutants in tumor cell migration and invasion

WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer.

p53 Isoforms: Key Regulators of the Cell Fate Decision.

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