Reduction of Ha-ras-induced cellular transformation by elevated expression of protein phosphatase type 2A

Abstract

The role of serine/threonine protein phosphatase type 2A (PP2A) in cellular growth control has not yet been thoroughly established. Earlier experiments with okadaic acid, a phosphatase inhibitor, suggested that PP2A may act as an anti-oncogene, although a direct role for this enzyme in the transformation process has not been demonstrated. We therefore investigated whether altered levels of PP2A expression would affect the transformation of mouse fibroblasts by the Ha-ras oncogene. Here we report that cells with elevated levels of PP2A expression were more resistant to focus formation induced by Ha-ras. At the molecular level, this was paralleled by the reduced Ha-ras-stimulated expression of the c-fos promoter, a proto-oncogene target for Ha-ras signaling. Thus, our results support a negative role for PP2A in the process of cellular transformation and may ascribe tumor-suppressing functions to this enzyme.

Protein phosphatase 1α activity prevents oncogenic transformation

“…In two other ways however, our data are reminiscent of the results obtained for PP2A. First, like PP1, PP2A inhibits oncogenic transformation at only 30%–50% activity increase [28]. In the case of PP1, the apparently small activity increase might be misleading as most of the overexpressed activity may be directed against certain substrates, such as pRb.…”

“…In the case of PP1, the apparently small activity increase might be misleading as most of the overexpressed activity may be directed against certain substrates, such as pRb. Second, like PP1, PP2A inhibits transformation in a transient transfection assay [28]. As can be expected in such an experiment, we were unable to detect PP1α (in the form of GFP fluorescence) in cells at the time of the transformation assays, that is, 2–3 wks after transfection.…”

“…Because the PP1α protein is effective for at least 3 d after electroporation [20], we reasoned that transient transfection might be suitable to examine whether PP1α can interfere with oncogenic transformation. This strategy has also been used successfully with PP2A [28]. Because transformation assays have been very well characterized for NIH 3T3 cells, we decided to perform these experiments with this cell line.…”

PP2A activity is controlled by methylation and regulates oncoprotein expression in melanoma cells: A mechanism which participates in growth inhibition induced by chloroethylnitrosourea treatment

“…At this dose, OA has been reported to increase cell proliferation (20). In our experiment, OA at 5 nM slightly stimulated cell growth (+30%, p<0.05) when compared to untreated cells (UN) (Fig.…”

Protein phosphatase 1α is a Ras‐activated Bad phosphatase that regulates interleukin‐2 deprivation‐induced apoptosis

“…Recently, a direct correlation between Ras activation and PP1/PP2A activation has been shown (Baharians and Schönthal, 1999; Rajesh et al ., 1999; Sieburth et al ., 1999). In addition, we have shown that Ras activation leads to apoptotic cell death upon IL‐2 deprivation, which is prevented by expression of the dominant‐negative Ras mutant N17 (Gómez et al ., 1998).…”