p63 Overexpression Induces the Expression of Sonic Hedgehog

Abstract

p63 and p73 are members of the p53 protein family and have been shown to play an important role in cell death, development, and tumorigenesis. In particular, p63 has been shown to be involved in the maintenance of epidermal stem cells and in the stratification of the epidermis. Sonic Hedgehog (Shh) is a morphogen that has also been implicated to play a role in epithelial stem cell proliferation and in the development of organs. Recently, Shh has also been shown to play an important role in the progression of a variety of cancers. In this report, we show that p63 and p73 but not p53 overexpression induces Shh expression. In particular, p63; and p63B (both TA and #N isoforms) and TAp73B isoform induce Shh. Expression of Shh was found to be significantly reduced in mouse embryo fibroblasts obtained from p63À/À mice. The naturally occurring p63 mutant TAp63;(R279H) and the tumor suppressor protein p14 ARF inhibited the TAp63;-mediated transactivation of Shh. The region À228 to À102 bp of Shh promoter was found to be responsive to TAp63;-induced transactivation and TAp63; binds to regions within the Shh promoter in vivo.

p63 consensus DNA-binding site: identification, analysis and application into a p63MH algorithm

“…Further studies are needed to determine if PTPN14 and ING1 are direct transcriptional targets of p63. The functional REs in other target genes recently reported as uniquely regulated by p63 and not p53, such as Shh (Caserta et al, 2006), IKKa (Candi et al, 2006) and PKCg (Ponassi et al, 2006), further support our description of the p63 consensus DNA-binding site and its functional impact on target selectivity in the p53 family.…”

p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

“…SHH is a downstream transcriptional target of p63 and its expression is reduced in p63-null urothelium (13,36). In keeping with our observations during development, SHH-expressing basal cells of the adult urothelium were recently shown to give rise to umbrella cells during normal homeostasis and after urothelial cell injury (37).…”

Gli Transcription Factors Mediate the Oncogenic Transformation of Prostate Basal Cells Induced by a Kras-Androgen Receptor Axis

“…Our results support the reciprocal regulation of Gli signaling and p63 expression for maintenance of the epidermal homeostasis of multiple organs, including normal prostate development (32). Interference with the p63 and Gli signaling interaction network leads to dysregulation of differentiation and promotes initiation of carcinogenesis (22,32,33).…”

“…Although the homeostasis of p63 expression dictates the differentiation and renewal of prostate progenitor cells, dysregulation of p63 expression promotes tumor progression (22). However, the regulation of p63 expression and the role of p63-expressing cells in prostate tumor progression remain unclear under pathological conditions.…”