TGF-β upregulates the translation of USP15 via the PI3K/AKT pathway to promote p53 stability

Crosstalk between transforming growth factor beta (TGF-beta) signaling and p53 has a critical role in cancer progression. TGF-beta signals via Smad and non-Smad pathways. Under normal conditions, wild-type p53 forms a complex with Smad2/3 and co-activates transcription of a variety of tumor suppressor genes, resulting in tumor suppressive effects. Thus, p53 stability is essential in progression of tumor suppressive responses mediated by TGF-beta signaling. However, it remains unknown whether p53 stability is regulated by TGF-beta. In the current study, we identify that USP15 binds to and stabilizes p53 through deubiquitination in U2OS and HEK293 cells. TGF-beta promotes the translation of USP15 through activation of mammalian target of rapamycin by the phosphoinositide 3-kinase/AKT pathway. Upregulation of USP15 translation links the crosstalk between TGF-beta signaling and p53 stability, allowing this cytokine to have a critical role in cancer progression.