p53 associates with and targets ΔNp63 into a protein degradation pathway

Abstract

A human p53 homologue, p63 (p40͞p51͞p73L͞CUSP) that maps to the chromosomal region 3q27-29 was found to produce a variety of transcripts that encode DNA-binding proteins with and without a trans-activation domain (TA-or ⌬N-, respectively). The p63 gene locus was found to be amplified in squamous cell carcinoma, and overexpression of ⌬Np63 (p40) led to increased growth of transformed cells in vitro and in vivo. Moreover, p63-null mice displayed abnormal epithelial development and germ-line human mutations were found to cause ectodermal dysplasia. We now demonstrate that certain p63 isotypes form complexes with p53. p53 mutations R175H or R248W abolish the association of p53 with p63, whereas V143A or R273H has no effect. Deletion studies suggest that the DNA-binding domains of both p53 and p63 mediate the association. Overexpression of wild type but not mutant (R175H) p53 results in the caspase-dependent degradation of certain ⌬Np63 proteins (p40 and ⌬Np63␣). The association between p53 and ⌬Np63 supports a previously unrecognized role for p53 in regulation of ⌬Np63 stability. The ability of p53 to mediate ⌬Np63 degradation may balance the capacity of ⌬Np63 to accelerate tumorigenesis or to induce epithelial proliferation.

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

“…We further looked for a possible contribution of p21 (also called p21 WAF1 , p21 sdi1 , p21 cip1 and Ink4A) to cell cycle control, since its elevated expression is well known to induce cell cycle arrest and was shown to be transactivated by TAp51 isoforms, which in turn is inhibited by DN isoforms (Yang et al, 1998;Ratovitski et al, 2001). Unexpectedly, we found that neither exogenous expression of TAp51B nor DNp51B influenced p21 promoter activity in keratinocytes (Figure 4d).…”

“…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)).…”

p51/p63 inhibits ultraviolet B-induced apoptosis via Akt activation

“…Subsequently, UV-B-irradiated cells with irreparable damage would promote p51 downregulation triggered by its phosphorylation (Papoutsaki et al, 2005;Westfall et al, 2005). Furthermore, p53 activated after the initial delay period following damage would promote DNp51B degradation (Ratovitski et al, 2001;Waltermann et al, 2003) and inhibits Akt activation (Stambolic et al, 2001), thereby eliminating cells with irreparable DNA damage by inducing apoptosis. This mechanism implies that mutation of p53 will not only make keratinocytes defective in p53-dependent apoptosis, but also will allow DNp51B to escape from p53-dependent degradation, leading to excess accumulation of DNp51B protein.…”

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

“…Since wild-type p53 protein mediates degradation of DNp63 in vitro (Ratovitski et al, 2001) and actually p53 mutations strongly relate to overexpression of DNp63 in squamous cell carcinoma (Hibi et al, 2000), we investigated the possible association of p53 status with impaired DNp63 expression in urothelial carcinoma. The p53 status was assessed by immunohistochemistry using the PAb1801 antibody (Esrig et al, 1993;Koga et al, 2000).…”