Regulation of the tumor suppressor PTEN by DNp63a

Abstract

<p>The p53 homolog p63 is critical for the development of all epithelial tissues. The predominant isoform, DNp63a, helps maintain the proliferative potential of basal epithelial cells and is also upregulated in a subset of cancers implicating it as a possible oncogene. Although DNp63a can reduce apoptosis via Akt activation, the exact mechanism by which this occurs is unknown. Given that the PI3KjAkt pathway is antagonized by the tumor suppressor PTEN, we investigated whether DNp63a is able to regulate PTEN levels in order to modulate the activity of Akt. Using overexpression studies we found that DNp63a reduced PTEN levels leading to the activation of Akt, while silencing DNp63a led to increased PTEN and a reduction in phosphorylated Akt. Loss of DNp63a further enhanced PTEN levels when coupled with the PI3K inhibitor LY294002. Chromatin immunoprecipitation and luciferase assays confirmed PTEN as a direct transcriptional target of DNp63a, with response elements distinct from those of p53. Consistent with its role as a tumor suppressor, loss of PTEN led to increased cell proliferation while loss of DNp63a reduced the proliferative capability of two skin cell lines. Interestingly, concomitant loss of DNp63a and PTEN returned cell growth levels to that of control suggesting that a regulatory loop exists between PTEN/Akt/ DNp63a in order to maintain appropriate levels of cell growth.</p><p>This presentation occurred at the Wright State University Campus-Wide Celebration of Research, Scholarship and Creative Activities on April 16, 2010</p>