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.

iASPP is a novel autophagy inhibitor in keratinocytes

“…7E) explores the contribution of iASPP to the apoptotic cell death response. We have recently shown that iASPP is involved in the maintenance of epidermal homeostasis, regulating genes that are essential for the cell adhesion, differentiation and proliferation of stratified epithelia (Chikh et al, 2011). Here, we have reinforced the notion of a constitutive anti-apoptotic function of iASPP, the expression of which is sufficient to repress apoptosis.…”

“…1A). To understand the molecular mechanisms underlying the resistance to apoptosis demonstrated by iASPPdepleted keratinocytes, we evaluated the expression levels of PMAIP1, the gene encoding Noxa, which we found to be downregulated in our previously published microarray analysis of iASPP-depleted cells (Chikh et al, 2011) (Fig. 1B).…”

“…Autophagy is a metabolic process of central importance in cell fate decisions, as it can either protect cells by preventing apoptosis or can result in cell death (Lum et al, 2005;Ravikumar and Rubinsztein, 2006). In our previous report, we demonstrated that iASPP is crucial for the fine-tuning of homeostasis in the basal layer of the epidermis (Chikh et al, 2011). Keratinocytes silenced for iASPP generated a markedly thicker epidermis, demonstrating that depletion of iASPP promotes and accelerates differentiation while simultaneously inhibiting the proliferation process in the stratified epidermis of the skin.…”

“…Two recent molecular studies have shown that iASPP is expressed from early stages of development through to adult epidermis, where it partially colocalizes with p63 (encoded by TP63) (Chikh et al, 2011;Notari et al, 2011). Moreover, a novel autoregulatory feedback mechanism functioning between iASPP and p63 has been identified in keratinocytes, whereby p63 modulates iASPP, and iASPP directly represses two previously unreported miRNAs, miR-720 and miR-574-3p, which, in turn, control the expression of the DNp63 isoform by preventing its translation.…”

p53/p63/p73 in the Epidermis in Health and Disease

“…Furthermore, p63 directly inhibits expression of miR-138, miR-181a/b, and miR130b in primary human keratinocytes (Rivetti di Val Cervo et al 2012). In turn, p63 expression in epidermal keratinocytes is regulated by miR-203, miR-720, and miR-574-3p, which are expressed in cells within the suprabasal epidermal layer and restrict p63 expression to basal cells (Yi et al 2008;Chikh et al 2011). In addition to the hair bulb, epidermal progenitors generate the sebaceous gland, which secretes sebum via the duct penetrating the upper part of the follicular epithelium and extrudes it into the hair follicle infundibulum (Niemann and Horsley 2012).…”