p63 Suppresses non-epidermal lineage markers in a bone morphogenetic protein-dependent manner via repression of Smad7.
p63, a p53 family member, plays an essential role in epidermal development by regulating its transcriptional program. Here we report a previously uncovered role of p63 in controlling bone morphogenetic protein (BMP) signaling, which is required for maintaining low expression levels of several non-epidermal genes. p63 represses transcription of the inhibitory Smad7 and activates Bmp7, thereby sustaining BMP signaling. In the absence of p63, compromised BMP signaling leads to inappropriate non-epidermal gene expression in postnatal mouse keratinocytes and in embryonic epidermis. Reactivation of BMP signaling by Smad7 knockdown and/or, to a lesser extent, by BMP treatment suppresses expression of non-epidermal genes in the absence of p63. Canonical BMP/Smad signaling is essential for control of non-epidermal genes as use of a specific inhibitor, or simultaneous knockdown of Smad1 and Smad5 counteract suppression of non-epidermal genes. Our data indicate that p63 prevents ectopic expression of non-epidermal genes by a mechanism involving Smad7 repression and, to a lesser extent, Bmp7 induction, with consequent enhancement of BMP/Smad signaling.
De Rosa
Laura
L
CEINGE Biotecnologie Avanzate, via Comunale Margherita 482, 80145 Napoli, Italy.
Antonini
Dario
D
Ferone
Giustina
G
Russo
Monia T
MT
Yu
Paul B
PB
Han
Rong
R
Missero
Caterina
C
D000818:Animals; D015415:Biomarkers; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D019070:Cell Lineage; D002478:Cells, Cultured; D000078404:Epidermal Cells; D005786:Gene Expression Regulation; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D010750:Phosphoproteins / Q000502:physiology*; D015398:Signal Transduction; D051906:Smad7 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D015534:Trans-Activators / Q000502:physiology*
D015415:Biomarkers; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D010750:Phosphoproteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D015534:Trans-Activators; C486419:Trp63 protein, mouse