The p63 gene is expressed as TAp63 from the P1 promoter and as Delta Np63 from the P2 promoter. Through alternative splicing, five TA and five Delta N isoforms (a-epsilon) are expressed. Isoforms alpha-beta and d share an identical 3'untranslated region (3'UTR) whereas isoform. has a unique 3'UTR. Recently, we found that RBM38 RNA-binding protein is a target of p63 and RBM38 in turn regulates p63 alpha/beta expression via mRNA stability. However, it is uncertain whether p63 gamma has a unique biological activity and whether p63 gamma is regulated by RBM38. Here, we found that the levels of Delta Np63 gamma transcript and protein are induced upon overexpression of RBM38 but decreased by RBM38 knockdown. Conversely, we found that the levels of Delta Np63 gamma transcript and protein are decreased by ectopic expression of RBM38 but increased by RBM38 knockdown, consistent with our previous report. Interestingly, RBM38 increases the half-life of p63 gamma mRNA by binding to a GU-rich element in p63 gamma 3'UTR. In contrast, our previous studies showed that RBM38 decreases the half-life of p63 alpha/beta mRNAs by binding to AU-/U-rich elements in their 3'UTR. We also found that knockout of p63 gamma in ME180 and HaCaT cells, in which Delta Np63 isoforms are predominant, inhibits cell proliferation and migration, suggesting that Delta Np63 gamma has a pro-growth activity. In contrast, we found that knockout of TAp63 gamma in MIA PaCa-2 cells, in which TAp63 isoforms are predominant, promotes cell proliferation, migration, and inhibits cellular senescence. Taken together, we conclude that Delta Np63 gamma has an oncogenic poten-tial whereas TAp63 gamma is a tumor suppressor.
