The transcription factor p63, a member of the p53 family, plays a crucial role in epithelial development and tumorigenesis through the regulation of epithelial progenitor cell proliferation, differentiation and apoptosis. Similarly to p53, p63 activity is regulated by post-translational modifications, including ubiquitylation. Here, we report that the WWP1 E3 ubiquitin ligase binds specifically to Delta Np63 isoform but it does not trigger Delta Np63 proteasome-dependent degradation. Accordingly, we found that WWP1-dependent ubiquitylation of Delta Np63 occurs through the formation of Lys63-linked poly-ubiquitin chains. Importantly, we found that WWP1 is able to increase Delta Np63-dependent transcription and depletion of WWP1 in human primary keratinocytes induces cell cycle arrest. All together these results indicate that WWP1 regulates Delta Np63 transcriptional activity, acting thus as a potential regulator of the proliferation and survival of epithelial-derived cells. (C) 2010 Elsevier Inc. All rights reserved.