A Truncated Isoform of the Protein Phosphatase 2A B56γ Regulatory Subunit May Promote Genetic Instability and Cause Tumor Progression
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F10, a subline of the B16 mouse melanoma cell line, is itself the parent of the more metastatic BL6 line. BL6 cells differ from F10 cells by an alteration of the gene encoding the B56gamma regulatory subunit of protein phosphatase 2A (PP2A), which results in the expression of a truncated variant of the subunit (Deltagamma1). PP2A is involved in regulating the cell-cycle checkpoint and we found that the checkpoint in BL6 cells is aberrant when the Deltagamma1 protein is expressed. That is, although Deltagamma1 protein levels in cultured BL6 cells are low and these cells do not show an altered checkpoint on gamma-irradiation, irradiated footpad BL6 tumor cells show both a marked increase in Deltagamma1 levels and more extensive polyploidy and less apoptosis than F10 cells. These observations were reproduced with Deltagamma1 gene-transfected F10 cells (F10(Deltagamma1)). Deltagamma1 expression and an aberrant checkpoint are also associated with a higher metastatic ability because irradiated F10(Deltagamma1) tumors metastasized much more frequently than F10 tumors, which rarely metastasized whether irradiated or not. Nonirradiated F10(Deltagamma1) tumors, which do not express Deltagamma1 protein, had similarly low rates of metastasis. The greater metastatic ability of irradiated F10(Deltagamma1) tumors also correlated with the acquisition of many more genomic alterations. Thus, it seems that Deltagamma1 expression may damage the checkpoint, which may then allow the acquisition of genetic alterations that promote metastasis. These observations support the notion that mechanisms promoting the genetic instability of tumors could also aid tumor progression from the nonmetastatic to the metastatic state.
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The role of B′ subunits as tumor suppressors is corroborated by the notion that B′ subunit knockdown causes polyploidy.
“This notion corroborates with the previous notion on the role of B′ subunits as tumor suppressors [45–49].”
From PP2A-B′ holoenzyme substrate recognition, regulation and role in cytokinesis (2017) · cites this paper as [46]
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- Authors
- Ito, A., Koma, Y.-I., Watabe, K., Nagano, T., Endo, Y., Nojima, H., & Kitamura, Y.
- Affiliations
- Osaka University Hospital (JP)
- The University of Osaka (JP)
- Fukushima Medical University (JP)
- Corresponding author
- Ito, Akihiko
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2003-01
- Volume
- 162
- Issue
- 1
- Pages
- 81-91
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1851121
- OpenAlex
- W2005246083
- Cited by
- 24
- References
- 41
- Citations by year
- 2021: 1 · 2020: 1 · 2019: 1 · 2017: 1 · 2012: 1
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Foundation for Promotion of Cancer Research
- Naito Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- protein phosphatase 2A, truncated protein isoform, melanoma, tumor progression, metastasis, genomic instability, cell cycle checkpoints, gamma irradiation, polyploidy, apoptosis, genetic alterations
- MeSH terms
- Animals, Cell Cycle, Cell Division, Cell Survival, Cell Transformation, Neoplastic, DNA Mutational Analysis, Gamma Rays, Isoenzymes, Lung Neoplasms, Melanoma, Experimental, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasm Transplantation, Phosphoprotein Phosphatases, Tumor Cells, Cultured, Tumor Stem Cell Assay, 3T3 Cells, Sequence Deletion, Disease Progression, Genes, cdc, Protein Subunits, Mice, Protein Phosphatase 2
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