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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
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    Life Sciences Publications

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      Recruitment of the complete hTREX complex is required for Kaposi's sarcoma-associated herpesvirus intronless mRNA nuclear export and virus replication

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      A cellular pre-mRNA undergoes various post-transcriptional processing events, including capping, splicing and polyadenylation prior to nuclear export. Splicing is particularly important for mRNA nuclear export as two distinct multi-protein complexes, known as human TREX (hTREX) and the exon-junction complex (EJC), are recruited to the mRNA in a splicing-dependent manner. In contrast, a number of Kaposi's sarcoma-associated herpesvirus (KSHV) lytic mRNAs lack introns and are exported by the virus-encoded ORF57 protein. Herein we show that ORF57 binds to intronless viral mRNAs and functions to recruit the complete hTREX complex, but not the EJC, in order assemble an export component viral ribonucleoprotein particle (vRNP). The formation of this vRNP is mediated by a direct interaction between ORF57 and the hTREX export adapter protein, Aly. Aly in turn interacts directly with the DEAD-box protein UAP56, which functions as a bridge to recruit the remaining hTREX proteins to the complex. Moreover, we show that a point mutation in ORF57 which disrupts the ORF57-Aly interaction leads to a failure in the ORF57-mediated recruitment of the entire hTREX complex to the intronless viral mRNA and inhibits the mRNAs subsequent nuclear export and virus replication. Furthermore, we have utilised a trans-dominant Aly mutant to prevent the assembly of the complete ORF57-hTREX complex; this results in a vRNP consisting of viral mRNA bound to ORF57, Aly and the nuclear export factor, TAP. Strikingly, although both the export adapter Aly and the export factor TAP were present on the viral mRNP, a dramatic decrease in intronless viral mRNA export and virus replication was observed in the absence of the remaining hTREX components (UAP56 and hTHO-complex). Together, these data provide the first direct evidence that the complete hTREX complex is essential for the export of KSHV intronless mRNAs and infectious virus production.
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