ΔNp63 induces β-catenin nuclear accumulation and signaling

Abstract

The P53 homolog p63 encodes multiple proteins with transactivating, apoptosis-inducing, and oncogenic activities. We showed that p63 is amplified and that DeltaNp63 isotypes are overexpressed in squamous cell carcinoma (SCC) and enhance oncogenic growth in vitro and in vivo. Moreover, p53 associated with DeltaNp63alpha and mediated its degradation. Here, we report that DeltaNp63 associates with the B56alpha regulatory subunit of protein phosphatase 2A (PP2A) and glycogen synthase kinase 3beta (GSK3beta), leading to a dramatic inhibition of PP2A-mediated GSK3beta reactivation. The inhibitory effect of DeltaNp63 on GSK3beta mediates a decrease in phosphorylation levels of beta-catenin, which induces intranuclear accumulation of beta-catenin and activates beta-catenin-dependent transcription. Our results suggest that DeltaNp63 isotypes act as positive regulators of the beta-catenin signaling pathway, providing a basis for their oncogenic properties.

Impaired ΔNp63 expression associates with reduced β-catenin and aggressive phenotypes of urothelial neoplasms

“…A recent in vitro study has shown that DNp63 plays a role in regulating b-catenin levels (Patturajan et al, 2002). Therefore, we investigated the possible association of p63 expression status and b-catenin expression pattern.…”

“…Therefore, p63 is unlikely to be a tumour suppressor gene that conforms to the two-hit model of carcinogenesis. On the other hand, DNp63 is considered to have oncogenic properties based on the following observations: (1) DNp63 overexpression is often observed (Parsa et al, 1999;Hibi et al, 2000) and it enhances oncogenic growth in squamous cell carcinomas (Hibi et al, 2000); (2) DNp63 could function as dominant negatives against the p53 tumour suppressor activities (Yang et al, 1998); and (3) DNp63 overexpression induces nuclear accumulation of b-catenin and activates the b-catenin signalling that promotes cell proliferation (Patturajan et al, 2002).…”

Identification of vitamin D receptor as a target of p63

“…Thus increasing the levels of TAp63 with chemotherapy could also lead to an increase in VDR expression and subsequently enhance the effectiveness to the VD analogues. Another possible mechanism by which p63g-mediated VDR expression may play a role in cancer could be through regulation of b-catenin pathway (Patturajan et al, 2002). VDR activation has been shown to induce differentiation by inhibition of the b-catenin signaling pathway (Palmer et al, 2001).…”

p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

“…The use of distal promoter generates TAp51 isoforms with transactivation domain (TA domain) in their NH 2 -terminus, capable of transactivating various p53 responsive promoters. The use of the proximal promoter generates DNp51 isoforms with a short peptide substituting for the TA domain, which exert dominant-negative activity against TA isoforms and p53 (Yang et al, 1998;Hibi et al, 2000;Ratovitski et al, 2001;Patturajan et al, 2002;Stiewe et al, 2002;Wu et al, 2003). In addition, both isoforms undergo three alternative splicing events at the COOH-terminus generating six different isoforms (reviewed by Ikawa et al (1999); Yang and McKeon (2000); Mills (2006)).…”