A truncated isoform of the protein phosphatase 2A B56gamma regulatory subunit may promote genetic instability and cause tumor progression.
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.
Ito
Akihiko
A
Department of Pathology, Osaka University Medical School, Suita, Japan. aito@patho.med.osaka-u.ac.jp
Koma
Yu-Ichiro
Y
Watabe
Kenji
K
Nagano
Teruaki
T
Endo
Yuichi
Y
Nojima
Hiroshi
H
Kitamura
Yukihiko
Y
D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle / Q000528:radiation effects; D002455:Cell Division / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005720:Gamma Rays; D018816:Genes, cdc / Q000528:radiation effects; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary*; D008546:Melanoma, Experimental / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000235:genetics / Q000503:physiopathology*; D009368:Neoplasm Transplantation; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism*; D054648:Protein Phosphatase 2; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D014410:Tumor Stem Cell Assay
D007527:Isoenzymes; D021122:Protein Subunits; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2