Cabrera J.R.,Consejo Superior Of Investigaciones Cientificasautonomous University Of Madrid |
Cabrera J.R.,CSIC - Biological Research Center |
Viejo-Borbolla A.,Consejo Superior Of Investigaciones Cientificasautonomous University Of Madrid |
Martinez-Martin N.,Consejo Superior Of Investigaciones Cientificasautonomous University Of Madrid |
And 4 more authors.
PLoS Pathogens | Year: 2015
Herpes simplex virus type 1 (HSV-1) and HSV-2 are highly prevalent viruses that cause a variety of diseases, from cold sores to encephalitis. Both viruses establish latency in peripheral neurons but the molecular mechanisms facilitating the infection of neurons are not fully understood. Using surface plasmon resonance and crosslinking assays, we show that glycoprotein G (gG) from HSV-2, known to modulate immune mediators (chemokines), also interacts with neurotrophic factors, with high affinity. In our experimental model, HSV-2 secreted gG (SgG2) increases nerve growth factor (NGF)-dependent axonal growth of sympathetic neurons ex vivo, and modifies tropomyosin related kinase (Trk)A-mediated signaling. SgG2 alters TrkA recruitment to lipid rafts and decreases TrkA internalization. We could show, with microfluidic devices, that SgG2 reduced NGF-induced TrkA retrograde transport. In vivo, both HSV-2 infection and SgG2 expression in mouse hindpaw epidermis enhance axonal growth modifying the termination zone of the NGF-dependent peptidergic free nerve endings. This constitutes, to our knowledge, the discovery of the first viral protein that modulates neurotrophins, an activity that may facilitate HSV-2 infection of neurons. This dual function of the chemokine-binding protein SgG2 uncovers a novel strategy developed by HSV-2 to modulate factors from both the immune and nervous systems. © 2015 Cabrera et al.
Navarro D.,Consejo Superior Of Investigaciones Cientificasautonomous University Of Madrid |
Agra N.,Consejo Superior Of Investigaciones Cientificasautonomous University Of Madrid |
Agra N.,Institute Salud Carlos III |
Pestana A.,Consejo Superior Of Investigaciones Cientificasautonomous University Of Madrid |
And 3 more authors.
Carcinogenesis | Year: 2010
Tumours of the Ewing family, which comprise Ewing's sarcoma and peripheral primitive neuroectodermal tumours, are highly aggressive and mostly affect children and adolescents. They are characterized by chromosomal translocations leading to the generation of fusion proteins between EWS (or very rarely FUS) and members of the E-twenty-six (ETS) family of transcription factors that are capable of transforming cells. EWS/FLI1, the most frequent fusion, is thought to cause transformation through activation or repression of specific target genes. We present evidence demonstrating that the Wnt inhibitor and β-catenin/T-cell factor (TCF)-responsive gene DICKKOPF-1 (DKK-1) is a transcriptional target of EWS/FLI1, which can inhibit both basal and β-catenininduced transactivation of the DKK-1 promoter. Moreover, our data indicate that EWS/FLI1 has a more general effect on β-catenin/TCF-mediated transcription since it can block transactivation of a consensus β-catenin/TCF reporter construct. Consistently, Ewing tumour cells expressing different EWS/ETS translocations cannot engage β-catenin/TCF-dependent transcription, whereas silencing of EWS/FLI1 restores β-catenin responsiveness in A673 and RD-ES Ewing tumour cells. Accordingly, gene set enrichment analysis shows that β-catenin/TCF target genes are significantly enriched among genes downregulated by EWS/FLI1 in the Ewing cell line A673. Mechanistically, the inhibitory effect of EWS/FLI1 can be overcome by a constitutively active TCF4 protein (TCF4-VP16). Moreover, EWS/FLI1 binds lymphoid enhancer factor 1, a TCF family member, and interferes with its binding to β-catenin, which could explain its negative effect on β-catenin/TCF-mediated transcription. Our results show that EWS/FLI1 inhibits both DKK-1 expression as well as β-catenin/TCF-dependent transcription, which could contribute to progression of tumours of the Ewing family. © The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.