Alteration or Inhibition of PP2A Is Essential in Human Cancer Development

When it was proposed over 10 years ago that PP2A might be a tumor suppressor [27], based on findings that okadaic acid acts as a potent tumor promoter as well as a strong inhibitor of PP2A, most regulatory B subunits had not yet been discovered and our view of PP2A was much simpler. Now it is clear that PP2A exists in numerous forms, some of which might suppress growth (see later discussion), while others might be growth stimulatory [28,29]. Strong support for the idea that PP2A is involved in growth control comes from the discovery that SV40 small T antigen and polyoma virus small T and middle T antigen form stable complexes with PP2A (Fig. 1) [2,11]. Of particular interest are two recent publications on the role of SV40 small T in the transformation of primary human cells. Yu et al. [30] reported that the transformation of primary human diploid fibroblasts and of mesothelial cells in culture depends on both SV40 large T and small T. Transformation of human cells does not occur without SV40 small T, and small T cannot be replaced by oncogenic Ras, in contrast to primary rodent cells, which can be transformed by the combination of SV40 large T and oncogenic Ras. Expression of telomerase is not required for transformation of human cells but only for growth beyond the point of senescence [30]. Similar results were reported by Hahn et al. [31] using human fibroblasts and human embryonic kidney cells. However, these authors found that Ras is required for transformation in addition to SV40 large T and small T, and transformation does not occur in the absence of either Ras or small T. This difference in Ras requirement between these two studies could be due to the time at which the transformation assay was scored (one group scored earlier than the other), the amount of small T expressed (one group used retroviral vectors, the other transfection), or the difference in cell type (K. Rundell, personal communication). The importance of both reports lies in the recognition that inhibition or alteration of PP2A by SV40 small T is required for transformation of primary human diploid fibrob-lasts and epithelial cells. In addition, transformation requires inactivation of p53 and pRb by complex formation with SV40 large T. Expression of telomerase is essential for the purpose of immortalization.

Further evidence for the importance of SV40 small T in transformation comes from experiments showing that human mesothelial cells expressing SV40 large T and small T are easier to transform by carcinogens than cells expressing large T only [32]. The potency of small T was also demonstrated in a transgenic mouse model in which only small T is expressed in breast epithelial tissue under the control of the acidic milk protein promoter [33]. Cyclin D1 is constitutively overex-pressed in the small-T-expressing mammary epithelial cells, and mammary gland differentiation is inhibited. Importantly, 10% of the transgenic animals develop breast tumors. In contrast, transgenic mice expressing only large T in breast epithelium develop breast cancer at a lower rate and after a longer latency period [33].

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