An Autoregulatory Loop Directs the Tissue-Specific Expression of p63 through a Long-Range Evolutionarily Conserved Enhancer

Abstract

p63, a p53 family member, is essential for the development of various stratified epithelia and is one of the earliest markers of many ectodermal structures, including the epidermis, oral mucosa, apical ectodermal ridge, and mammary gland. Genetic regulatory mechanisms controlling p63 spatial expression during development have not yet been defined. Using a genomic approach, we identified an evolutionarily conserved cis-regulatory element, located 160 kb downstream of the first p63 exon, which functions as a keratinocyte-specific enhancer and is sufficient to recapitulate expression of the endogenous gene during mouse embryogenesis. Dissection of the p63 enhancer activity revealed a positive autoregulatory loop in which the p63 proteins directly bind to and are essential regulators of the enhancer. Accordingly, transactivating p63 isoforms induce endogenous p63 expression in cells that do not normally express this gene, whereas dominant negative isoforms suppress p63 expression in keratinocytes. In addition the transcription factor AP-2 also binds to the enhancer and cooperates with p63 to induce its activity. These results demonstrate that a long-range autoregulatory loop is involved in the regulation of p63 expression during embryonic development and in adult cells.

p63 and p73 in human cancer: defining the network

“…These findings imply a potential negative feedback loop that may restrict p53 and TAp73-dependent transcription. Both positive and negative regulation of DNp63 mRNA and protein have been shown by different groups to be mediated by both p53 and DNp63 itself (Harmes et al, 2003;Waltermann et al, 2003;Antonini et al, 2006;Romano et al, 2006). DNp63 may also be positively regulated by TAp63g in a manner that is independent of p53, suggesting yet another possible feedback mechanism (Li et al, 2006).…”

Regulation of skin aging and heart development by TAp63

“…17,58 Finally, a specific activity of a strong p63 enhancer was reported in the embryonic heart area of transgenic mice. 59 As stated above, p63 expression was detected by in situ hybridization in the branchial (pharyngeal) arches, where cardiac progenitors are located and reside close to ectodermal and endodermal progenitor cells before their migration to the cardiac tube. 60 The embryonic pharyngeal arch contain tbx1-positive cells that originate from the neural crest and have a vital role in heart development.…”

Cell density‐dependent acetylation of ΔNp63α is associated with p53‐dependent cell cycle arrest

“…The epidermal stem cell-specific expression of DNp63a is first induced at the transcription level, and the stem cell-specific transcriptional elements are being partially characterized [21,22]. P63 protein also undergoes extensive post-translational modifications, which regulate its stability and function.…”