The Essential Role of p53 in Hyperpigmentation of the Skin via Regulation of Paracrine Melanogenic Cytokine Receptor Signaling

Daiki Murase,Akira Hachiya,Yasuko Amano,Atsushi Ohuchi,Takashi Kitahara,Yoshinori Takema

doi:10.1074/jbc.m805570200

Daiki Murase, Akira Hachiya + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m805570200

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Abstract

Hyperpigmentation of the skin is characterized by increases in melanin synthesis and deposition. Although considered a significant psychosocial distress, little is known about the detailed mechanisms of hyperpigmentation. Recently, the tumor suppressor protein p53 has been demonstrated to promote ultraviolet B-induced skin pigmentation by stimulating the transcription of a melanogenic cytokine, POMC (pro-opiomelanocortin), in keratinocytes. Given that p53 can be activated by various kinds of diverse stresses, including sun exposure, inflammation, and aging, this finding led us to examine the involvement of p53 in cytokine receptor signaling, which might result in skin hyperpigmentation. Immunohistochemical and reverse transcription-PCR analyses revealed the increased expression and phosphorylation of p53 in the epidermis of hyperpigmented spots, accompanied by the higher expression of melanogenic cytokines, including stem cell factor, endothelin-1, and POMC. The involvement of p53 in hyperpigmentation was also indicated by the significantly higher expression of p53 transcriptional targets in the epidermis of hyperpigmented spots. Treatment of human keratinocytes and melanocytes with known p53 activators or inhibitors, including pifithrin-alpha (PFT), demonstrated significant increases or decreases, respectively, in the expression of melanogenic factors, including cytokines and their receptors. Additionally, PFT administration abolished stem cell factor-induced phosphorylation of mitogen-activated protein kinase in human melanocytes. Furthermore, when organ-cultured hyperpigmented spots, in vitro human skin substitutes, and mouse skin were treated with PFT or p53 small interfering RNA, the expression of melanogenic cytokines and their receptors was significantly decreased, as were levels of tyrosinase and melanogenesis. Taken together, these data reveal the essential role of p53 in hyperpigmentation of the skin via the regulation of paracrine-cytokine signaling, both in keratinocytes and in melanocytes.

Highlights

Hyperpigmentation generally results from three major steps in the epidermis: the proliferation of melanocytes, the synthesis and activation of tyrosinase to produce melanin, and the transfer of melanosomes to keratinocytes [1,2,3,4]
During the first two steps, a complicated network composed of paracrine and autocrine cytokines secreted by keratinocytes and by melanocytes, respectively, plays an important role in regulating melanogenesis in collaboration with their corresponding receptors, whose expression is regulated by various cytokines [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23]
Those findings suggest that the biphasic expression of SCF and ET-1 intrinsically plays a pivotal role in the proliferation and melanogenesis of human melanocytes in vivo during UVB-induced hyperpigmentation

Summary

Introduction

Hyperpigmentation generally results from three major steps in the epidermis: the proliferation of melanocytes, the synthesis and activation of tyrosinase to produce melanin, and the transfer of melanosomes to keratinocytes [1,2,3,4]. Quantitative real time RT-PCR analysis demonstrated significant increases in mRNA transcript levels of well known melanogenic paracrine cytokines (i.e. SCF, ET-1, and POMC, in the pigmented spots compared with peripheral control areas (Fig. 1C), which is consistent with previous studies [26, 27, 32].

Results

Conclusion