BACKGROUND: The role of p53 in the pathogenesis of skin diseases such as plaque-type psoriasis has long been questioned but never resolved. OBJECTIVES: In this study we set out to determine the contribution of p53 activity to defective interfollicular epidermal skin differentiation in a murine hyperproliferative skin model. METHODS: We used the tamoxifen-inducible K14MycER mouse model which exhibits abnormal epidermal differentiation in response to high MYC activity, crossed with p53 knock-out mice. Results- We show that genetic deletion of p53 leads to improvements in granular layer formation. Furthermore, we show that p53 activity regulates down-stream expression of Keratin 6a, Pparb/d and Pparg and is regulated upstream by retinoic acid signalling-dependent mechanisms. CONCLUSION: We conclude aberrant non-apoptotic p53 activity contributes, in-part, to abnormal differentiation and granular layer defects. This article is protected by copyright. All rights reserved.