The endocytosis inhibitors methyl-beta-cyclodextrin (M beta CD) and chlorpromazine enhanced surface localization of FGFR1 in PC12 cells and DRG neurons. Furthermore, M beta CD and chlorpromazine increased FGF-2-induced neurite outgrowth of PC12 cells
and axonal branching of adult DRG neurons overexpressing FGFR1, whereas M beta CD inhibited FGF-2-induced axonal elongation. Analysis of the signaling pathways involved in axon morphology revealed that FGF-2-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was increased by inhibition of FGFR1 endocytosis. AZD7762 datasheet Together, our results imply that inhibition of FGFR1 endocytosis by M beta CD or chlorpromazine promotes FGF-2-induced axonal branching. The results of this study confirm that internalization of FGFR1 controls axon growth and morphology of adult sensory neurons via selective activation of intracellular signaling pathways. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Human parainfluenza virus type 1 (HPIV1) is an important respiratory pathogen in young children, the immunocompromised, and the elderly. We found that infection with wild-type (WT) HPIV1 suppressed the innate immune response in human airway epithelial cells by preventing not only phosphorylation of interferon regulatory factor 3 (IRF3) but also degradation
Rigosertib nmr of I kappa B beta, thereby inhibiting IRF3 and NF-kappa B activation, respectively. Both of these effects were ablated by a F170S substitution in the HPIV1 C proteins (F170S) or by silencing the C open reading frame [P(C-)], resulting in a potent beta interferon (IFN-beta) response. Using murine knockout cells, we found that IFN-beta induction following infection with
either mutant relied mainly on melanoma-associated differentiation gene 5 (MDA5) rather than retinoic acid-inducible gene I (RIG-I). Infection with either mutant, but not WT HPIV1, induced a significant accumulation of intracellular double-stranded RNA (dsRNA). These mutant viruses directed a marked increase in the accumulation of viral genome, antigenome, and mRNA that was coincident with the accumulation of dsRNA. In addition, the amount of viral proteins was reduced compared to that of WT HPIV1. Thus, the accumulation of dsRNA might be a result of an either imbalance in the N protein/genomic RNA ratio leading to incomplete encapsidation. Protein kinase R (PKR) activation and IFN-beta induction followed the kinetics of dsRNA accumulation. Interestingly, the C proteins did not appear to directly inhibit intracellular signaling involved in IFN-beta induction; instead, their role in preventing IFN-beta induction appeared to be in suppressing the formation of dsRNA. PKR activation contributed to IFN-beta induction and also was associated with the reduction in the amount of viral proteins.