Nuclear hormone receptor functions in keratinocyte and melanocyte homeostasis, epidermal carcinogenesis and melanomagenesis

Abstract

Edited by Laszlo NagyKeywords: Skin Keratinocyte Melanocyte Homeostasis Type II nuclear hormone receptor Signaling Melanoma Atopic dermatitis Inflammation SCC BCC a b s t r a c t Skin homeostasis is maintained, in part, through regulation of gene expression orchestrated by type II nuclear hormone receptors in a cell and context specific manner. This group of transcriptional regulators is implicated in various cellular processes including epidermal proliferation, differentiation, permeability barrier formation, follicular cycling and inflammatory responses. Endogenous ligands for the receptors regulate actions during skin development and maintenance of tissue homeostasis. Type II nuclear receptor signaling is also important for cellular crosstalk between multiple cell types in the skin. Overall, these nuclear receptors are critical players in keratinocyte and melanocyte biology and present targets for cutaneous disease management.

Mutation inKANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair

“…They are composed of a ligand-binding domain and DNA-binding domain, which interact with regulatory regions on target genes, leading to their activation or repression 13. Nuclear receptors play an important role in maintaining skin homeostasis, and they are involved in a myriad of cellular functions, including epidermal differentiation, proliferation, formation of the permeability barrier, follicular cycling and inflammatory reactions 14. Their function is tightly regulated by a number of corepressors and coactivators, of which proteins from the steroid receptor coactivator (SRC) family are especially important 15.…”

RORα and ROR γ are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20‐hydroxy‐ and 20,23‐dihydroxyvitamin D

“…Examples of this are the production and processing of cholesterol, a necessary element of the epidermal barrier (14) and the precursor to locally produced steroids (15), and production and activation of vitamin D (16, 17). These molecules interact with nuclear receptors expressed in resident skin cells to regulate homeostasis of this organ (13, 18–20). Skin also has the ability to produce and metabolize melatonin (21), a molecule originally considered to be an endogenous ligand for RORα (22), but this role has been questioned (23, 24).…”

Lipoxin A4 inhibits proliferation and inflammatory cytokine/chemokine production of human epidermal keratinocytes associated with the ERK1/2 and NF-κB pathways

“…Keratinocytes constitute approximately 90% of the adult epidermis. Many reports have indicated that keratinocytes play an important role in inflammatory skin disease and cutaneous tumors [10,11]. In resting keratinocytes, immune factors are low.…”