Cutaneous pigment formation and aberration in disease are addressed. Dynoodt et al. (this issue) present data on a specific micro RNA that downregulates proteins involved in melanogenesis and ...melanosome movement. Kim et al. (this issue) present data showing that Wnt signaling is involved in the pathogenesis of melasma. Both articles enhance our understanding of cutaneous pigmentation and point to targets in the development of novel therapeutic modalities.
Neurotrophins in Skin Biology and Pathology Botchkarev, Vladimir A.; Yaar, Mina; Peters, Eva M.J. ...
Journal of investigative dermatology,
08/2006, Letnik:
126, Številka:
8
Journal Article
Recenzirano
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Neurotrophins (NTs) belong to a family of growth factors, which control the development, maintenance, and apoptotic death of neurons and also fulfill multiple regulatory functions outside the nervous ...system. Biological effects induced by NTs strongly depend on the pattern of NT receptor/co-receptors expression in target cells, as well as on the set of intracellular adaptor molecules that link NT signalling to distinct biochemical pathways. In this review, we summarize data on the molecular mechanisms underlying the involvement of NTs in the control of non-neuronal functions in normal skin (e.g. keratinocyte proliferation, melanocyte development and apoptosis, hair growth). We also review the data on the role for NTs and their receptors in a number of pathological skin conditions (stress-induced hair loss, psoriasis, atopic dermatitis). Although additional efforts are required to fully understand mechanisms underlying the involvement of NTs and their receptors in controlling functions of normal and pathologically altered skin cells, substantial evidence suggests that modulation of NT signalling by NTs receptor agonists/antagonists may be developed as intervention modalities in distinct skin and hair growth pathologies.
Skin cancer incidence is clearly linked to UV irradiation and increases exponentially with age. We studied the rate of removal of thymine dimers and (6–4) photoproducts in UV‐irradiated human dermal ...fibroblasts derived from donors of different ages. There was a significant decrease with aging in the repair rates of both thymine dimers and (6–4) photoproducts (P< 0.001). In addition, there was an age‐associated decrease in the protein levels of ERCC3, PCNA, RPA, XPA, and p53 that participate in nucleotide excision repair. Moreover, the mRNA levels of XPA, ERCC3, and PCNA were significantly reduced with aging, suggesting that these decreases are often regulated at the mRNA level. Furthermore, with age induction of p53 after UV irradiation was significantly reduced. Taken together, our data suggest that the age‐associated decrease in the repair of UV‐induced DNA damage results at least in part from decreased levels of proteins that participate in the repair process.—Goukassian, D., Gad, F., Yaar, M., Eller, M. S., Nehal, U. S., Gilchrest, B. A. Mechanisms and implications of the age‐associated decrease in DNA repair capacity. FASEB J. 14, 1325–1334 (2000)
Abstract Background Reactive oxygen species (ROS) are generated by cellular metabolism as well as by exogenous agents. While ROS can promote cellular senescence, they can also act as signaling ...molecules for processes that do not lead to senescence. Telomere homolog oligonucleotides (T-oligos) induce adaptive DNA damage responses including increased DNA repair capacity and these effects are mediated, at least in part, through p53. Objective Studies were undertaken to determine whether such p53-mediated protective responses include enhanced antioxidant defenses. Methods Normal human fibroblasts as well as R2F fibroblasts expressing wild type or dominant negative p53 were treated with an 11-base T-oligo, a complementary control oligo or diluents alone and then examined by western blot analysis, immunofluorescence microscopy and various biochemical assays. Results We now report that T-oligo increases the level of the antioxidant enzymes superoxide dismutase 1 and 2 and protects cells from oxidative damage; and that telomere-based γH2AX (DNA damage) foci that form in response to T-oligos contain phosphorylated ATM and Chk2, proteins known to activate p53 and to mediate cell cycle arrest in response to oxidative stress. Further, T-oligo increases cellular ROS levels via a p53-dependent pathway, and these increases are abrogated by the NAD(P)H oxidase inhibitor diphenyliodonium chloride. Conclusion These results suggest the existence of innate telomere-based protective responses that act to reduce oxidative damage to cells. T-oligo treatment induces the same responses and offers a new model for studying intracellular ROS signaling and the relationships between DNA damage, ROS, oxidative stress, and cellular defense mechanisms.
Bone morphogenetic proteins (BMPs), members of the transforming growth factor-β family, signal in many cells including neural precursors. Two receptors, types 1 and 2, coordinately mediate BMP ...signaling, and type 1 receptor has two forms: A and B. Using RT-PCR we found that neural crest-derived human melanocytes express BMP receptor-1A, -1B, and -2. Furthermore, melanocytes and the surrounding keratinocytes express BMP-4, suggesting both autocrine and paracrine effects of this molecule. Moreover, BMP-4 supplementation of cultured human melanocytes decreases melanin synthesis, tyrosinase mRNA, and protein. The mechanism of this BMP-4 effect on tyrosinase and ultimately on melanogenesis involves modest decreases of tyrosinase transcription rate and mRNA stability. Moreover, ultraviolet irradiation, the best recognized environmental stimulator of melanogenesis, down-regulated the mRNA of BMP receptor-1B in melanocytes. Our data provide evidence of a novel regulatory pathway for melanogenesis in human skin.
Keratinocytes in human skin undergo apoptosis during various inflammatory processes and after ultraviolet (UV) irradiation. To determine if keratinocyte apoptosis may be mediated by the Fas/APO-1 ...receptor (CD95), a signal transduction pathway known to initiate programmed cell death of lymphocytes, we investigated Fas expression, modulation, and function in keratinocytes. Keratinocytes constitutively expressed the 2.5- and 1.9-kb Fas transcripts, as well as the 43-kDa Fas protein. Treatment of interferon-γ-stimulated keratinocytes with Fas agonistic antibody significantly promoted their cell death, indicating that Fas in keratinocytes is functional. UV irradiation induced Fas mRNA expression within 16 to 24 h and Fas protein within 24 h and through 48 h after irradiation. Furthermore, keratinocytes constitutively expressed Fas ligand (FasL) mRNA and protein. UV irradiation induced FasL mRNA as early as 4 h after irradiation and elevated FasL mRNA levels were maintained for at least 24 h postirradiation. Moreover, a FasL neutralizing antibody significantly reduced UV-induced apoptosis of IFN-γ-treated keratinocytes. Our data strongly suggest that the Fas system contributes to keratinocyte apoptosis in UV-irradiated human skin.
Work in the past 8 years, particularly in the past 1-2 years, has greatly expanded our understanding of the mechanisms by which ultraviolet irradiation stimulates melanogenesis in the skin. A direct ...effect of UV photons on DNA results in up-regulation of the gene for tyrosinase, the rate-limiting enzyme in melanin synthesis, as well as an increase in cell surface expression of receptors for at least one of the several known keratinocyte-derived melanogenic factors, MSH. Direct effects of UV on melanocyte membranes, releasing DAG and arachidonic acid, may also play a role in the tanning response. Diacylglycerol may activate PKC-beta, which in turn phosphorylates and activates tyrosinase protein; the pathways by which products of other inflammatory mediator cascades may act on melanogenesis are unknown. The tanning response also relies heavily on UV-stimulated increased production and release of numerous keratinocyte-derived factors including bFGF, NGF, endothelin-1 and the POMC-derived peptides MSH, ACTH, beta-LPH and beta-endorphin. These factors variably induce melanocyte mitosis, increase melanogenesis, enhance dendricity and prevent apoptotic cell death following the UV injury. Thus, events within the epidermal melanin unit conspire to maintain or increase melanocyte number, increase melanin pigment throughout the epidermis. Overall, ultraviolet-induced melanogenesis may be one part of a eukaryotic SOS response to damaging ultraviolet irradiation that has evolved over time to provide a protective tan in skin at risk of further injury from sun exposure. These recent insights into the mechanisms underlying ultraviolet-induced melanogenesis offer the opportunity for novel therapeutic approaches to minimizing acute and chronic photodamage in human skin.
Melanocytes are pigment-producing cells that originate from the dorsal portions of the closing neural tube in vertebrate embryos. Similar to neurons, they are derived from pluripotent neural crest ...cells that differentiate into numerous cell lineages. The development of melanocytes and neurons, as well as their differentiated function, within the mature tissue, is influenced by signaling molecules produced by neighboring cells. The same signaling molecules that have a role in the central and peripheral nervous tissue also have a role in cutaneous melanocytes. These include Wnt, bone morphogenetic proteins, endothelins, steel factor, hepatocyte growth factor, fibroblast growth factors, and neurotrophins. Signaling pathways including PKC- and p53/p73-dependent pathways are also common to melanocytes and neurons. The similarity between melanocytes and neurons suggests that melanocytes could provide a valuable model for studies of diseases that affect the nervous system, as well as for development of potential therapies for these diseases.
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