p53 activity contributes to defective interfollicular epidermal differentiation in hyperproliferative murine skin

DEAR EDITOR, Skin diseases affect a significant percentage of the population and are often the result of a complex interplay between autoimmune dysregulation, and abnormal epidermal differentiation and proliferation. Origins may be genetic and/ or environmental, and while no complete cure exists for conditions such as psoriasis, a range of treatments, including reti-noids and antibodies against tumour necrosis factor-a and interleukin-17, have shown therapeutic efficacy, although relapses can occur. 1 While there is no definitive mouse model for psoriasis, some do present with abnormal skin phenotypes that have revealed interesting molecular drivers. 1 For example, agonist-treated peroxisome proliferator-activated receptor (PPAR) b/d transgenic mice develop psoriasis-like conditions with failed compaction of the granular layer, which can be countered by PPARb/d antagonists. 2 PPARb/d is also upregu-lated in human psoriasis and murine ichthyosis, 2,3 but has proinflammatory, anti-inflammatory and prodifferentiation properties in various contexts. 4,5 PPARc, although predominantly expressed in the sebaceous gland, has similar prodiffer-entiation effects, and can reduce inflammation and promote barrier formation in mice with induced parakeratosis (Fig. S1; see Supporting Information). 6 The tumour suppressor p53 is upregulated in the pathogen-esis of human chronic plaque-type psoriasis (Fig. 1a), and its role in skin disease has long been questioned. 7 In additional animal studies, p53 has been found to be largely dispensable to epidermal homeostasis, with gene loss only causing minor alterations in murine catagen, 8 and paradoxically, p53 deletion reduces oncogenesis in transgenic mouse skin carcinogenesis studies. 9 p53 knockdown also promotes squamous differentiation in human keratinocytes cultured in vitro, 10 which suggests p53 activation may impair keratinocyte differentiation in the interfollicular epidermis; however, this has not been tested in vivo. A parakeratotic differentiation programme can be invoked by high MYC activity in keratinocytes; thus, K14MycER mice form a useful model of hyperproliferative skin. They overex-press MYC fused with the tamoxifen-responsive mutant oestrogen receptor ligand binding domain in the keratin 14 (K14)-positive basal layer of the epidermis and, upon activation with high-dose 4-hydroxytamoxifen (4OHT), exhibit parakeratotic lesions of acanthosis, hyperkeratosis and dermal inflammatory infiltration (see Fig. S1; see Supporting Information). 11,12 Our K14MycER mice also show dose-dependent activation of the tumour suppressor p53 (Fig. 1b). 13 We previously crossed K14MycER mice with p53 knockout animals and demonstrated that aberrant p53 activity interferes with sebaceous gland differentiation by impairing androgen receptor function. 13 In this study we investigated if p53 activity also contributes to defective interfollicular epidermal differentiation in …