Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN~(+/-) mice by the p85 regulatory subunits of phosphoinositide 3-kinase

摘要

Mice with heterozygous deletion of the PTEN tumor suppressor gene develop a range of epithelial neoplasia as well as lymphoid hyperplasia. Previous studies suggest that PTEN suppresses tumor formation by acting as a phosphoinositide phosphatase to limit signaling by phosphoinositide 3-kinase (PI3K). Here, we examined the effect of deleting various regulatory subunits of PI3K (p85α and p85β) on epithelial neoplasia and lymphoid hyperplasia in PTEN~(+/-) mice. Interestingly, we found the loss of one p85α allele with or without the loss of p85β led to increased incidence of intestinal polyps. Signaling downstream of PI3K was enhanced in the PTEN~(+/-)p85α~(+/-)p85β~(-/-) polyps, as judged by an increased fraction of both cells with cytoplasmic staining of the transcription factor FKHR and cells with positive staining for the proliferation marker Ki-67. In contrast, the incidence of prostate intraepithelial neoplasia was not significantly altered in PTEN~(+/-) mice heterozygous for p85α or null for p85β, whereas the fraction of proliferating cells in prostate intraepithelial neoplasia was reduced in mice lacking p85β. Finally, there was no significant change in T lymphocyte hyperplasia in the PTEN~(+/-) mice with various p85 deletions, although anti-CD3-stimulated AKT activation was somewhat reduced in the p85α~(+/-) background. These results indicate that decreasing the levels of different p85 regulatory subunits can result in enhanced PI3K signaling in some tissues and decreased PI3K signaling in others, supporting the model that, although p85 proteins are essential for class I_A PI3K signaling, they can function as inhibitors of PI3K signaling in some tissues and thus suppress tumor formation.