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ig 1. (a)
Molecular pathway of tanning. Tanning is the result of a complex
signalling pathway involving keratinocytes and melanocytes. Many genes
associated with pigmentation phenotypes and skin cancer susceptibility
participate in this signalling. Ultraviolet (UV) radiation reaching
keratinocytes leads to the production of a large number of cytokines (shown
in greater detail in b). In particular, it leads to α-melanocyte
stimulating hormone (α-Msh) production through a p53-dependent pathway.
This pathway begins with UV-induced photoproduct formation triggering a
repair response mediated by the xeroderma pigmentosum (XP) DNA repair
enzymes. Genetic injury also stimulates a DNA damage response mediated
in part by the ataxia-telangiectasia-related (ATR) gene product and p53.
In cases of severe damage, p53 may induce apoptosis while in other cases
p53 triggers cell cycle arrest and the expression of pro-opiomelanocortin
(POMC) – the precursor protein for α-Msh.33α-Msh
is secreted from keratinocytes and binds to Mc1r on nearby melanocytes
causing the increased production of pigment (shown in greater detail in
c and d). This increased pigment is transferred to nearby keratinocytes
where it provides modest protection against later UV exposure. (b) UV
radiation stimulates the expression of many cytokines by keratinocytes.
Many of these have effects on melanocytes and are reviewed elsewhere.22 GMCSF,
granulocyte-macrophage colony-stimulating factor; ET1, endothelin-1;
bFGF, basic fibroblast growth factor; SCF, stem cell factor. (c) The
primary gene governing pigmentation is MC1R,
which encodes a 7-pass transmembrane G-protein coupled receptor
expressed on melanocytes that responds to the POMC derivative α-Msh and
controls the expression of red-yellow vs. brown-black melanin pigments.
Mc1r activation stimulates adenylate cyclase (AC), which in turn
increases cyclic adenosine monophosphate (cAMP) production, the
phosphorylation of cAMP response element-binding protein (Creb) through
protein kinase A (PKA), and microphthalmia transcription factor (MITF)
expression.55 Mitf
activity can be affected by c-kit activity through the mitogen activated
protein kinase (MAPK) pathway.64 Increased
Mitf activity then induces the expression of a variety of genes involved
in pigment synthesis or melanosome function including tyrosinase (TYR),
dopachrome tautomerase (DCT),
tyrosinase-related protein 1 (TYRP1)65 and
protein kinase C-beta (PKC-B).66 Other
genes are able to affect this pathway directly including agouti
signalling protein (ASIP)
which biochemically functions to antagonize Mc1r.67 Expression
of ASIP is
itself regulated by the bone morphogenic protein (BMP)
pathway wherein Noggin sequesters BMP, preventing its binding to cognate
receptors, and decreases the expression of ASIP.68 (d)
Pigmentation is a reflection of the type and quantity of two major
pigments produced by melanocytes. Eumelanin is dark brown-black, while
phaeomelanin is yellow-red. Signalling through Mc1r increases the
production of the brown-black pigment. The production of both pigments
begins with the rate-limiting oxidation of tyrosine to DOPAquinone by
the enzyme tyrosinase. Additional enzymes including dopachrome
tautomerase and tyrosinase-related protein 1 convert DOPAquinone into
other intermediate products. Two different eumelanin pigments, which
differ in colour and solubility, are formed from the further oxidation
of these various compounds. Alternatively, the availability of cysteine
or glutathione causes DOPAquinone to be converted into phaeomelanin.69,70 The
mixed ratio of the two pigments, eumelanin and phaeomelanin, determine
final hair and skin colour.71,72
A.J. Miller and H. Tsao*New insights into pigmentary pathways and skin
cancer British Journal of Dermatology 2010 162, pp22–28
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