p63 overexpression induces the expression of Sonic Hedgehog.
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.
Caserta
Tina M
TM
Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH 45435, USA.
Kommagani
Ramakrishna
R
Yuan
Ziqiang
Z
Robbins
David J
DJ
Mercer
Carol A
CA
Kadakia
Madhavi P
MP
D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology
C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C000606460:TP73 protein, human; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins