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The essential role of p53 in hyperpigmentation of the skin via regulation of paracrine melanogenic cytokine receptor signaling
- Source :
- The Journal of biological chemistry. 284(7)
- Publication Year :
- 2008
-
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.
- Subjects :
- Keratinocytes
medicine.medical_specialty
Aging
Pro-Opiomelanocortin
Transcription, Genetic
MAP Kinase Signaling System
Ultraviolet Rays
medicine.medical_treatment
Stem cell factor
Human skin
Skin Pigmentation
Biology
Biochemistry
Paracrine signalling
Mice
Internal medicine
Paracrine Communication
medicine
Animals
Humans
Benzothiazoles
Receptors, Cytokine
Molecular Biology
Inflammation
Melanins
Epidermis (botany)
Cell Biology
Middle Aged
Hyperpigmentation
Cell biology
Endocrinology
Cytokine
Epidermal Cells
Gene Expression Regulation
Skin hyperpigmentation
Cytokines
Melanocytes
Female
medicine.symptom
Epidermis
Tumor Suppressor Protein p53
Cytokine receptor
Toluene
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 284
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....87ef8d042df19034ad3f03994378b89e