A mutation in protein phosphatase type 2A as a cause of melanoma progression
A. Ito1, Y.-I. Koma1 and K. Watabe2
Departments of 1Pathology and 2Internal Medicine and Molecular Science, Osaka University Medical School, Yamada-oka, Suita, Osaka, Japan
Offprint requests to: Akihiko Ito, MD., Department of Pathology, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Fax: +81-6-6879-3729. e-mail: aito@patho.med.osaka-u.ac.jp
Summary. The BL6 subline was derived from the F10 line, which was derived from the B16 mouse melanoma cell line. BL6 cells are more invasive than F10 cells and differ genetically from F10 cells by an alteration of the gene encoding the B56g regulatory subunit of protein phosphatase 2A (PP2A). This alteration results in the transcription of mRNA encoding a truncated variant of the B56g1 isoform (Dg1). Dg1 is capable of targeting PP2A to the specific subcellular sites but incapable of promoting the dephosphorylation of specific substrates that is normally mediated by the B56g subunit-containing PP2A holoenzyme. It thus appears that activities of this type of holoenzymes decrease in cells expressing Dg1. Recently, we found two possible ways how Dg1 contributes to the enhanced metastatic potential of BL6 cells. The two ways seemed far away from each other: Dg1 influenced both the nuclear and cytoplasmic functions of the cell. In the cytoplasm, Dg1 localized at the Golgi complex and accelerated Golgi-mediated vesicle transport. On the other hand, Dg1 disturbed the cell-cycle regulation. In response to g-irradiation, protein levels of Dg1 were markedly increased in BL6 cells. Subsequently the integrity of cell-cycle checkpoint became more aberrant in BL6 cells than that in F10 cells. These two actions of Dg1 could results in the enhancement of the malignant phenotypes of melanoma cells, as discussed in this review. Histol. Histopathol. 18, 1313-1319 (2003)
Key words: B16 melanoma, PP2A, Genetic instability,
Checkpoint, Golgi complex, Migration
DOI: 10.14670/HH-18.1313