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

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-␣ (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.There are various types of hyperpigmentations (pigmented spots) of the skin characterized by increases in melanin synthesis and deposition, such as freckles, postinflammatory hyperpigmentation, UV-induced pigmentation (UV-melanoses), senile lentigines (age spots), pigmentation petaloides actinica, and melasma. These hyperpigmentations are well known to cause significant psychosocial distress, but little is known about their detailed mechanisms.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 (1-4). 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 also regulated by various cytokines (5-23). In addition, several types of c...

The inhibitory effect of a Platycodon root extract on ultraviolet B-induced pigmentation due to a decrease in Kit expression

“…Additionally, it was also confirmed that cell viability was not changed by the application of this extract to HSSs (data not shown). This inhibitory effect on melanin synthesis in HSSs was shown to be equal to that of pifithrin-α, the inhibitor of SCF-inducing phosphorylation of MAPK, as we previously reported [8]. Additionally, our clinical study revealed that application of this extract significantly depresses UVB-induced pigmentation even at 1 week after irradiation in a dose-dependent manner (Fig.…”

A Polymorphic p53 Response Element in KIT Ligand Influences Cancer Risk and Has Undergone Natural Selection

“…The transcriptional activation of KITLG upon p53 activation has been clearly demonstrated in multiple studies utilizing different cell types, different p53-activating stimuli and different measurement techniques (McGowan et al, 2008; Murase et al, 2009; Smeenk et al, 2011; Terzian et al, 2010; Wei et al, 2006). Consistent with this, we observed significant p53 binding to KITLG in the region that harbors the KITLG p53-RE SNP, in 10 out of 11 different cell line and treatment combinations (Figure 3A).…”

“…Specifically, KITLG and its receptor C-KIT are a part of a pathway that is known to be central in regulating proliferation, survival and migration of primordial germ cells, melanoblasts and hematopoietic stem cells (Lennartsson and Rönnstrand, 2012). In the pigmentary system, ultraviolet radiation induces p53-Kitlg signaling in keratinocytes, which in turn affects melanocytes that express the c-Kit receptor in order to mount a cutaneous UV response such as tanning (Murase et al, 2009). Interestingly, when we compared this response in mice either wild-type (WT) or null for p53 ( p53 null ), we noted dramatic differences.…”

Alpha-Melanocyte–Stimulating Hormone Suppresses Oxidative Stress through a p53-Mediated Signaling Pathway in Human Melanocytes

“…Our results unraveled a mechanism involving a-MSH and p53 in the adaptive response of melanocytes to UVR. Others have shown that p53 increases the expression of the melanogenic enzymes tyrosinase and tyrosine-related protein 1 (TYRP-1), suggesting its role in regulating melanogenesis (20,21). In mouse skin, p53 stimulates the expression of proopiomelanocortin (POMC), the precursor of a-MSH and adrenocorticotropic hormone (ACTH; refs.…”