Caserta Tina M, Kommagani Ramakrishna, Yuan Ziqiang, Robbins David J, Mercer Carol A, Kadakia Madhavi P
Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH 45435, USA.
Mol Cancer Res. 2006 Oct;4(10):759-68. doi: 10.1158/1541-7786.MCR-05-0149.
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, p63gamma and p63beta (both TA and DeltaN isoforms) and TAp73beta isoform induce Shh. Expression of Shh was found to be significantly reduced in mouse embryo fibroblasts obtained from p63-/- mice. The naturally occurring p63 mutant TAp63gamma(R279H) and the tumor suppressor protein p14(ARF) inhibited the TAp63gamma-mediated transactivation of Shh. The region -228 to -102 bp of Shh promoter was found to be responsive to TAp63gamma-induced transactivation and TAp63gamma binds to regions within the Shh promoter in vivo. The results presented in this study implicate p63 in the regulation of the Shh signaling pathway.
p63和p73是p53蛋白家族的成员，已被证明在细胞死亡、发育和肿瘤发生中发挥重要作用。特别是，p63已被证明参与表皮干细胞的维持和表皮的分层。音猬因子（Shh）是一种形态发生素，也被认为在上皮干细胞增殖和器官发育中起作用。最近，Shh也被证明在多种癌症的进展中发挥重要作用。在本报告中，我们表明p63和p73而非p53的过表达诱导Shh表达。特别是，p63γ和p63β（TA和DeltaN异构体）以及TAp73β异构体诱导Shh。在从p63基因敲除小鼠获得的小鼠胚胎成纤维细胞中，发现Shh的表达显著降低。天然存在的p63突变体TAp63γ（R279H）和肿瘤抑制蛋白p14（ARF）抑制TAp63γ介导的Shh反式激活。发现Shh启动子的-228至-102 bp区域对TAp63γ诱导的反式激活有反应，并且TAp63γ在体内与Shh启动子内的区域结合。本研究结果表明p63参与Shh信号通路的调控。
