Role of p63 in Development, Tumorigenesis and Cancer Progression

Abstract

The p53-related protein p63 has pleiotropic functions, including cell proliferation, survival, apoptosis, differentiation, senescence, and aging. The p63 gene is expressed as multiple isoforms that either contain an N-terminal p53-homologous transactivation domain (TAp63) or that lack this domain (ΔNp63). Multiple studies have demonstrated that p63 plays a crucial role in stratified epithelial development, and have shown the importance of p63 for maintaining proliferation potential, inducing differentiation, and preventing senescence. Additionally, much research focuses on the role of p63 in cancer progression. Clinical evidence suggests that p63 may play a role in inhibiting metastasis. Similarly, genetic mice models together with cell culture data strongly indicate that p63 deficiency may be a causative factor for metastatic spread. Moreover, the role of p63 in cancer metastasis has been shown to be greatly related to the ability of mutant p53 to promote cancer malignancy. However, there is still much confusion as to what the role of each specific isoform is. In this review, we highlight some of the major findings in the current literature regarding the role of specific p63 isoforms in development, tumorigenesis, and particularly in cancer metastasis.

Fig. 1

The p63 gene and protein structure. a The p63 gene (TP63) is encoded by sixteen exons and can be expressed from two different transcriptional start sites. Alternative splicing generates five different C-termini for a total of ten isoforms. b The p63 proteins contain six defined structural domains: An N-terminal transactivation domain (TA), a DNA binding domain (DBD), an oligomerization domain (OD), a second transactivation domain (TA2), a sterile alpha motif (SAM), and a post-inhibitory domain (PID). The TA domain, DBD, and OD are 22 %, 60 %, and 37 % homologous to the respective p53 domains

Fig. 2

The p63 protein inhibits metastasis via multiple mechanisms. a ΔNp63α has been shown to inhibit metastasis by a variety of molecular mechanisms, including negative regulation of Erk2 signaling, positive regulation of Id-3 signaling, and by maintaining cell adhesion in epithelial cells. b Under certain cellular conditions, TGFβ induces a trimeric complex between mutant p53 (mtp53), Smad2, and p63 that inactivates p63 activity. In this context, p63 is thought to inhibit metastasis by up-regulation of Sharp-1 and Cyclin G2 expression. c Mutant p53 may also inhibit p63 from promoting integrin recycling to the plasma membrane. Integrin recycling enhances PI3-K/Akt signaling, which induces cell motility and cancer metastasis. d TAp63 isoforms have been shown to inhibit metastasis by up-regulating DICER and miR-130b. The studies described above regarding mtp53 inhibition of p63 attribute anti-metastatic properties primarily to TAp63 isoforms, as these are the isoforms that are predominantly expressed in the systems used in these studies

Fig. 3

p63 is a metastasis inhibitor, while mutant p53 promotes malignancy. Mutant p53 (mtp53) may promote metastasis by inhibiting p63. Moreover, mtp53 may enhance metastatic spread via other mechanisms, and p63 can inhibit mtp53 from inducing metastasis. Thus, loss of p63 expression may cooperate with mtp53 to promote metastasis