Hair shaft melanin components (eu- or/and pheomelanin) are a long-lived record of precise interactions in the hair follicle pigmentary unit, e.g., between follicular melanocytes, keratinocytes, and dermal papilla fibroblasts. Follicular melanogenesis (FM) involves sequentially the melanogenic activity of follicular melanocytes, the transfer of melanin granules into cortical and medulla keratinocytes, and the formation of pigmented hair shafts. This activity is in turn regulated by an array of enzymes, structural and regulatory proteins, transporters, and receptors and their ligands, acting on the developmental stages, cellular, and hair follicle levels. FM is stringently coupled to the anagen stage of the hair cycle, being switched-off in catagen to remain absent through telogen. At the organ level FM is precisely coupled to the life cycle of melanocytes with changes in their compartmental distribution and accelerated melanoblast/melanocyte differentiation with enhanced secretory activity. The melanocyte compartments in the upper hair follicle also provides a reservoir for the repigmentation of epidermis and, for the cyclic formation of new anagen hair bulbs. Melanin synthesis and pigment transfer to bulb keratinocytes are dependent on the availability of melanin precursors, and regulation by signal transduction pathways intrinsic to skin and hair follicle, which are both receptor dependent and independent, act through auto-, para- or intracrine mechanisms and can be modified by hormonal signals. The important regulators are MC1 receptor its and adrenocorticotropic hormone, melanocyte stimulating hormone, agouti protein ligands (in rodents), c-Kit, and the endothelin receptors with their ligands. Melanin itself has a wide range of bioactivities that extend far beyond its determination of hair color.

The skin, a self-regulating protective barrier organ, is empowered with sensory and computing capabilities to counteract the environmental stressors to maintain and restore disrupted cutaneous homeostasis. These complex functions are coordinated by a cutaneous neuro-endocrine system that also communicates in a bidirectional fashion with the central nervous, endocrine, and immune systems, all acting in concert to control body homeostasis. Although UV energy has played an important role in the origin and evolution of life, UV absorption by the skin not only triggers mechanisms that defend skin integrity and regulate global homeostasis but also induces skin pathology (e.g., cancer, aging, autoimmune responses). These effects are secondary to the transduction of UV electromagnetic energy into chemical, hormonal, and neural signals, defined by the nature of the chromophores and tissue compartments receiving specific UV wavelength. UV radiation can upregulate local neuroendocrine axes, with UVB being markedly more efficient than UVA. The locally induced cytokines, corticotropin-releasing hormone, urocortins, proopiomelanocortin-peptides, enkephalins, or others can be released into circulation to exert systemic effects, including activation of the central hypothalamic-pituitary-adrenal axis, opioidogenic effects, and immunosuppression, independent of vitamin D synthesis. Similar effects are seen after exposure of the eyes and skin to UV, through which UVB activates hypothalamic paraventricular and arcuate nuclei and exerts very rapid stimulatory effects on the brain. Thus, UV touches the brain and central neuroendocrine system to reset body homeostasis. This invites multiple therapeutic applications of UV radiation, for example, in the management of autoimmune and mood disorders, addiction, and obesity.

Everyone knows and seems to agree that melanocytes are there to generate melanin -an intriguing, but underestimated multipurpose molecule that is capable of doing far more than providing pigment and UV protection to skin (1). What about the cell that generates melanin, then? Is this dendritic, neural crestderived cell still serving useful (or even important) functions when no-one looks at the pigmentation of our skin and its appendages and when there is essentially no UV exposure? In other words, what do epidermal and hair follicle melanocytes do in their spare time -at night, under your bedcover? How much of the full portfolio of physiological melanocyte functions in mammalian skin has really been elucidated already? Does the presence or absence of melanoctyes matter for normal epidermal and ⁄ or hair follicle functions (beyond pigmentation and UV protection), and for skin immune responses? Do melanocytes even deserve as much credit for UV protection as conventional wisdom attributes to them? In which interactions do these promiscuous cells engage with their immediate epithelial environment and who is controlling whom? What lessons might be distilled from looking at lower vertebrate melanophores and at extracutaneous melanocytes in the endeavour to reveal the 'secret identity' of melanocytes? The current Controversies feature explores these far too infrequently posed, biologically and clinically important questions. Complementing a companion viewpoint essay on malignant melanocytes (2), this critical re-examination of melanocyte biology provides a cornucopia of old, but underappreciated concepts and novel ideas on the slowly emerging complexity of physiological melanocyte functions, and delineates important, thought-provoking questions that remain to be definitively answered by future research. Praeludium pigmentosumFor those uninformed, the skin is an inert plastic wrap nature provides to keep us in and everything else out. How mistaken they are! The skin, in particular the epidermis, is one of the most active of all tissues ⁄ organs.Nature wisely placed the capillary circulation in the dermis. The epidermis has no vascular circulation thereby minimizing the probability that toxic chemicals, bacteria or fungi that penetrate through the stratum corneum can diffuse into the blood stream. That does not leave the epidermis defenseless. The epidermis has proteins called defensins that have anti-microbial properties. There are Toll-like receptors that recognize invading organisms and incite a host response. Even more interesting, it is well known that keratinocytes are avidly phagocytic. They have the capacity to phagocytize the wandering, invasive fungi or bacteria and digest them. It is both interesting and important that a-MSH stimulates the ingestion of candida by keratinocytes. a-MSH has a wide array of activities, only one of which is to stimulate the synthesis of melanin. There are receptors for a-MSH on Langerhans cells and keratinocytes as well as melanocytes. It has the ability to suppress infla...

Melanins form a diverse group of pigments synthesized in living organisms in the course of hydroxylation and polymerization of organic compounds. Melanin production is observed in all large taxa from both Pro- and Eukaryota. The basic functions of melanins are still a matter of controversy and speculation, even though their adaptative importance has been proved. Melanogenesis has probably evolved parallel in various groups of free living organisms to provide protection from environmental stress conditions, but in pathogenic microorganisms it correlates with an increased virulence. The genes responsible for melanization are collected in some cases within operons which find a versatile application in genetic engineering. This review summarizes current views on melanogenesis in Pro- and Eukaryotic microorganisms in terms of their biotechnological and biomedical importance.

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Purpose: Peroxisome proliferator-activated receptors (PPAR) regulate lipid and glucose metabolism but their anticancer properties have been recently studied as well.We previously reported the antimetastatic activity of the PPARa ligand, fenofibrate, against melanoma tumors in vivo.Here we investigated possible molecular mechanisms of fenofibrate anti metastatic action. Experimental Design: Monolayer cultures of mouse (B16F10) and human (SkMell88) melanoma cell lines, soft agar assay, and cell migration assay were used in this study. In addition, we analyzed PPARa expression and its transcriptional activity in response to fenotibrate by using Western blots and liciferase-based reporter system. Results: Fenofibrate inhibited migration of B16F10 and SkMel188 cells in Transwell chambers and colony formation in soft agar.These effects were reversed by PPAR inhibitor, GW9662. Western blot analysis revealed time-dependent down-regulation of Akt and extracellular signal^regu-lated kinase l/2 phosphorylation in fenofibrate-treated cells. A B16F10 cell line stably expressing constitutively active Akt mutant was resistant to fenofibrate. In contrast, Akt gene silencing with siRNA mimicked the fenofibrate action and reduced the migratory ability of B16F1O cells. In addition, fenofibrate strongly sensitized BI6FIO cells to the proapoptotic drug staurosporine, further supporting the possibility that fenofibrate-induced down-regulation of Akt function contributes to fenofibrate-mediated inhibition of metastatic potential in this experimental model. Conclusions: Our results show that the PPAR-dependent antimetastatic activity of fenofibrate involves down-regulation of Akt phosphorylation and suggest that supplementation with this drug may improve the effectiveness of melanoma chemotherapy.

The original strain of proopiomelanocortin (POMC)-deficient mice (Pomc Ϫ/Ϫ ) was generated by homologous recombination in 129X1/SvJ (A w /A w )-derived embryonic stem cells using a targeting construct that deleted exon 3, encoding all the known functional POMC-derived peptides including ␣MSH, from the Pomc gene. Although these Pomc Ϫ/Ϫ mice exhibited adrenal hypoplasia and obesity similar to the syndrome of POMC deficiency in children, their agouti coat color was only subtly altered. To further investigate the mechanism of hair pigmentation in the absence of POMC peptides, we studied wild-type (Pomc ϩ/ϩ ), heterozygous (Pomc ϩ/Ϫ ), and homozygous (Pomc Ϫ/Ϫ ) mice on a nonagouti (a/a) 129;B6 hybrid genetic background. All three genotypes had similar black fur pigmentation with yellow hairs behind the ears, around the nipples, and in the perianal area characteristic of inbred C57BL/6 mice. Histologic and electron paramagnetic resonance spectrometry examination demonstrated that hair follicles in back skin of Pomc Ϫ/Ϫ mice developed with normal structure and eumelanin pigmentation; corresponding molecular analyses, however, excluded local production of ␣MSH and ACTH because neither Pomc nor putative Pomc pseudogene mRNAs were detected in the skin. Thus, 129;B6 Pomc null mutant mice produce abundant eumelanin hair pigmentation despite their congenital absence of melanocortin ligands. These results suggest that either the mouse melanocortin receptor 1 has sufficient basal activity to trigger and sustain eumelanogenesis in vivo or that redundant nonmelanocortin pathway(s) compensate for the melanocortin deficiency. Whereas the latter implies feedback control of melanogenesis, it is also possible that the two mechanisms operate jointly in hair follicles. (Endocrinology 146: M ELANIN BIOSYNTHESIS IS initiated both in vitro andin vivo from the obligatory hydroxylation of ltyrosine to l-dihydroxyphenylalanine (L-DOPA), catalyzed by tyrosinase (EC 1.14.18.1) (1-3). Once L-DOPA is formed, further steps of melanogenesis consisting of a series of oxidoreduction reactions and intramolecular transformations can occur spontaneously and at varying rates, depending on local concentrations of hydrogen ions, metal cations, reducing agents, thiols, and oxygen (1). Eumelanogenesis involves the transformation of dopaquinone to leukodopachrome, followed by a series of oxidoreduction reactions with production of the intermediates dihydroxyindole and dihydroxyindole carboxylic acid, which undergo polymerization to form eumelanin (1,4,5). Pheomelanogenesis also starts with dopaquinone, which is conjugated to cysteine or glutathione to yield cysteinyldopa and glutathionyldopa for further transformation into pheomelanin (1,5,6).Although tyrosinase activity is the rate-limiting step among the melanogenesis-related enzymes (1,7,8), pigmentation is under complex genetic control regulated by more than 150 alleles representing more than 90 gene loci (3, 9 -14). Protein products of these loci include enzymes, structural proteins, transcriptional ...

The effect of fenofibrate, a ligand of peroxisome proliferator-activated receptor (PPAR) alpha, on the growth and metastatic potential of Bomirski hamster melanoma s.c. tumors, pigmented line (BHM Ma) was investigated in vivo. RT-PCR and Western-blot analyses revealed the presence of mRNA and protein of PPAR alpha in BHM Ma cells. The animals treated orally with fenofibrate developed significantly fewer metastatic foci in the lungs, as compared to the control group; however, primary tumor growth remained unaltered. This observation is interesting in respect of the potential use of fenofibrate in melanoma chemoprevention.