iASPP/p63 autoregulatory feedback loop is required for the homeostasis of stratified epithelia

iASPP, an inhibitory member of the ASPP (apoptosis stimulating protein of p53) family, is an evolutionarily conserved inhibitor of p53 which is frequently upregulated in human cancers. However, little is known about the role of iASPP under physiological conditions. Here, we report that iASPP is a cr...

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Published in:	The EMBO journal 2011-10, Vol.30 (20), p.4261-4273
Main Authors:	Chikh, Anissa, Matin, Rubeta N H, Senatore, Valentina, Hufbauer, Martin, Lavery, Danielle, Raimondi, Claudio, Ostano, Paola, Mello-Grand, Maurizia, Ghimenti, Chiara, Bahta, Adiam, Khalaf, Sahira, Akgül, Baki, Braun, Kristin M, Chiorino, Giovanna, Philpott, Michael P, Harwood, Catherine A, Bergamaschi, Daniele
Format:	Article
Language:	eng
Subjects:	Animals Cell Adhesion Cell adhesion & migration Cell Differentiation Cell Line Cell Proliferation Cells, Cultured differentiation Feedback, Physiological Gene Expression HEK293 Cells Homeostasis Humans iASPP Intracellular Signaling Peptides and Proteins - metabolism Keratinocytes - metabolism Membrane Proteins - metabolism Mice MicroRNAs - metabolism miRNA p63 Phosphoproteins - metabolism proliferation Repressor Proteins - metabolism RNA Interference Skin - metabolism Trans-Activators - metabolism
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Summary:	iASPP, an inhibitory member of the ASPP (apoptosis stimulating protein of p53) family, is an evolutionarily conserved inhibitor of p53 which is frequently upregulated in human cancers. However, little is known about the role of iASPP under physiological conditions. Here, we report that iASPP is a critical regulator of epithelial development. We demonstrate a novel autoregulatory feedback loop which controls crucial physiological activities by linking iASPP to p63, via two previously unreported microRNAs, miR‐574‐3p and miR‐720. By investigating its function in stratified epithelia, we show that iASPP participates in the p63‐mediated epithelial integrity program by regulating the expression of genes essential for cell adhesion. Silencing of iASPP in keratinocytes by RNA interference promotes and accelerates a differentiation pathway, which also affects and slowdown cellular proliferation. Taken together, these data reveal iASPP as a key regulator of epithelial homeostasis. This manuscript identifies an essential role for the p53 inhibitor iASPP in keratinocyte biology. By regulating two new microRNAs, iASPP controls p63, a key transcriptional regulator for the formation of stratified epithelia.
ISSN:	0261-4189 1460-2075