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    Bone morphogenetic proteins differentially regulate pigmentation in human skin cells

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    Publication date
    2012
    Author
    Singh, Suman K.
    Abbas, Waqas A.
    Tobin, Desmond J.
    Keyword
    Adult
    Aged
    Bone Morphogenetic Protein 4; Antagonists & inhibitors; Metabolism; Pharmacology
    Bone Morphogenetic Protein 6; Antagonists & inhibitors; Metabolism; Pharmacology
    Bone Morphogenetic Protein Receptors
    Coculture techniques
    Epidermis; Drug effects; Radiation effects
    Female
    Gene knockdown techniques
    Humans
    Keratinocytes; Enzymology
    Melanins; Biosynthesis
    Melanocytes; Ultrastructure
    Middle aged
    Models; Biological
    Monophenol Monooxygenase
    Myosins
    Pigmentation
    Pseudopodia
    Signal transduction
    Skin; cytology
    Smad Proteins
    Ultraviolet rays
    Up-Regulation
    p38 Mitogen-Activated Protein Kinases
    REF 2014
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    Abstract
    Bone morphogenetic proteins (BMPs) are a large family of multi-functional secreted signalling molecules. Previously BMP2/4 were shown to inhibit skin pigmentation by downregulating tyrosinase expression and activity in epidermal melanocytes. However, a possible role for other BMP family members and their antagonists in melanogenesis has not yet been explored. In this study we show that BMP4 and BMP6, from two different BMP subclasses, and their antagonists noggin and sclerostin were variably expressed in melanocytes and keratinocytes in human skin. We further examined their involvement in melanogenesis and melanin transfer using fully matched primary cultures of adult human melanocytes and keratinocytes. BMP6 markedly stimulated melanogenesis by upregulating tyrosinase expression and activity, and also stimulated the formation of filopodia and Myosin-X expression in melanocytes, which was associated with increased melanosome transfer from melanocytes to keratinocytes. BMP4, by contrast, inhibited melanin synthesis and transfer to below baseline levels. These findings were confirmed using siRNA knockdown of BMP receptors BMPR1A/1B or of Myosin-X, as well as by incubating cells with the antagonists noggin and sclerostin. While BMP6 was found to use the p38MAPK pathway to regulate melanogenesis in human melanocytes independently of the Smad pathway, p38MAPK, PI3-K and Smad pathways were all involved in BMP6-mediated melanin transfer. This suggests that pigment formation may be regulated independently of pigment transfer. These data reveal a complex involvement of regulation of different members of the BMP family, their antagonists and inhibitory Smads, in melanocytes behaviour.
    URI
    http://hdl.handle.net/10454/6194
    Citation
    Singh, S. K., Abbas, W. A., Tobin, D. J. (2012) Bone morphogenetic proteins differentially regulate pigmentation in human skin cells. Journal of Cell Science, 125 (Pt 18), 4306-19.
    Link to publisher’s version
    http://dx.doi.org/10.1242/jcs.102038
    Type
    Article
    Collections
    Life Sciences Publications

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      Bone morphogenetic protein antagonist noggin promotes skin tumorigenesis via stimulation of the Wnt and Shh signaling pathways

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      Bone morphogenetic proteins (BMPs) play pivotal roles in the regulation of skin development. To study the role of BMPs in skin tumorigenesis, BMP antagonist noggin was used to generate keratin 14-targeted transgenic mice. In contrast to wild-type mice, transgenic mice developed spontaneous hair follicle-derived tumors, which resemble human trichofolliculoma. Global gene expression profiles revealed that in contrast to anagen hair follicles of wild-type mice, tumors of transgenic mice showed stage-dependent increases in the expression of genes encoding the selected components of Wnt and Shh pathways. Specifically, expression of the Wnt ligands increased at the initiation stage of tumor formation, whereas expression of the Wnt antagonist and tumor suppressor Wnt inhibitory factor-1 decreased, as compared with fully developed tumors. In contrast, expression of the components of Shh pathway increased in fully developed tumors, as compared with the tumor placodes. Consistent with the expression data, pharmacological treatment of transgenic mice with Wnt and Shh antagonists resulted in the stage-dependent inhibition of tumor initiation, and progression, respectively. Furthermore, BMP signaling stimulated Wnt inhibitory factor-1 expression and promoter activity in cultured tumor cells and HaCaT keratinocytes, as well as inhibited Shh expression, as compared with the corresponding controls. Thus, tumor suppressor activity of the BMPs in skin epithelium depends on the local concentrations of noggin and is mediated at least in part via stage-dependent antagonizing of Wnt and Shh signaling pathways.
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      MSK1 regulates homeostatic and experience-dependent synaptic plasticity

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