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(American Journal of Pathology. 2003;162:81-91.)
© 2003 American Society for Investigative Pathology

Regular Articles

A Truncated Isoform of the Protein Phosphatase 2A B56{gamma} Regulatory Subunit May Promote Genetic Instability and Cause Tumor Progression

Akihiko Ito*, Yu-ichiro Koma*, Kenji Watabe{dagger}, Teruaki Nagano{ddagger}, Yuichi Endo§, Hiroshi Nojima{ddagger} and Yukihiko Kitamura*

From the Departments of Pathology* and Internal Medicine and Molecular Science,{dagger} Osaka University Medical School, Suita, Osaka; the Department of Molecular Genetics,{ddagger} Institute for Microbial Diseases, Osaka University, Suita, Osaka; and the Department of Biochemistry,§ Fukushima Medical College, Fukushima, Japan

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 B56{gamma} regulatory subunit of protein phosphatase 2A (PP2A), which results in the expression of a truncated variant of the subunit ({Delta}{gamma}1). PP2A is involved in regulating the cell-cycle checkpoint and we found that the checkpoint in BL6 cells is aberrant when the {Delta}{gamma}1 protein is expressed. That is, although {Delta}{gamma}1 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 {Delta}{gamma}1 levels and more extensive polyploidy and less apoptosis than F10 cells. These observations were reproduced with {Delta}{gamma}1 gene-transfected F10 cells (F10{Delta}{gamma}1). {Delta}{gamma}1 expression and an aberrant checkpoint are also associated with a higher metastatic ability because irradiated F10{Delta}{gamma}1 tumors metastasized much more frequently than F10 tumors, which rarely metastasized whether irradiated or not. Nonirradiated F10{Delta}{gamma}1 tumors, which do not express {Delta}{gamma}1 protein, had similarly low rates of metastasis. The greater metastatic ability of irradiated F10{Delta}{gamma}1 tumors also correlated with the acquisition of many more genomic alterations. Thus, it seems that {Delta}{gamma}1 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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