title: iASPP/p63 autoregulatory feedback loop is required for the homeostasis of stratified epithelia.
abstract: 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.
authors: Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK.
authors: Anissa
authors: A
authors: Chikh
authors: Rubeta N H
authors: RN
authors: Matin
authors: Valentina
authors: V
authors: Senatore
authors: Martin
authors: M
authors: Hufbauer
authors: Danielle
authors: D
authors: Lavery
authors: Claudio
authors: C
authors: Raimondi
authors: Paola
authors: P
authors: Ostano
authors: Maurizia
authors: M
authors: Mello-Grand
authors: Chiara
authors: C
authors: Ghimenti
authors: Adiam
authors: A
authors: Bahta
authors: Sahira
authors: S
authors: Khalaf
authors: Baki
authors: B
authors: Akgül
authors: Kristin M
authors: KM
authors: Braun
authors: Giovanna
authors: G
authors: Chiorino
authors: Michael P
authors: MP
authors: Philpott
authors: Catherine A
authors: CA
authors: Harwood
authors: Daniele
authors: D
authors: Bergamaschi
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D025461:Feedback, Physiological; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism*; D012867:Skin / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: C081876:CKAP4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C558811:MIRN574 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C119612:PPP1R13L protein, human; D010750:Phosphoproteins; C501916:Ppp1r13l protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse