Volume 22, No 10, Oct 2012

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 22 Issue 10, October 2012: 1479-1501

ORIGINAL ARTICLES

The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling

Chiara Sandri^1,2,*, Francesca Caccavari^1,2,*, Donatella Valdembri^1,2,*, Chiara Camillo^1,2, Stefan Veltel³, Martina Santambrogio^1,2, Letizia Lanzetti^2,4, Federico Bussolino ¹Laboratory of Cell Adhesion Dynamics, Institute for Cancer Research and Treatment (IRCC), Strada Provinciale 142, Km 3.95, 10060 Candiolo (TO), Italy
²Department of Oncological Sciences, University of Torino School of Medicine, 10060 Candiolo (TO), Italy
³University of Turku Centre for Biotechnology and VTT Medical Biotechnology, FIN-20520, Turku, Finland
⁴Laboratory of Membrane Trafficking, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (TO), Italy
⁵Laboratory of Vascular Oncology, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (TO), Italy
⁶Center for Complex Systems in Molecular Biology and Medicine ?SysBioM ?University of Torino, c/o Department of Animal and Human Biology (DBAU), 10123 Torino, Italy Correspondence: Guido Serini,(guido.serini@ircc.it)

>Although HCO₃⁻ is known to be required for early embryo development, its exact role remains elusive. Here we report that HCO₃⁻ acts as an environmental cue in regulating miR-125b expression through CFTR-mediated influx during preimplantation embryo development. The results show that the effect of HCO₃⁻ on preimplantation embryo development can be suppressed by interfering the function of a HCO₃⁻-conducting channel, CFTR, by a specific inhibitor or gene knockout. Removal of extracellular HCO₃⁻ or inhibition of CFTR reduces miR-125b expression in 2 cell-stage mouse embryos. Knockdown of miR-125b mimics the effect of HCO₃⁻ removal and CFTR inhibition, while injection of miR-125b precursor reverses it. Downregulation of miR-125b upregulates p53 cascade in both human and mouse embryos. The activation of miR-125b is shown to be mediated by sAC/PKA-dependent nuclear shuttling of NF-κB. These results have revealed a critical role of CFTR in signal transduction linking the environmental HCO₃⁻ to activation of miR-125b during preimplantation embryo development and indicated the importance of ion channels in regulation of miRNAs.

Cell Research (2012) 22:1479-1501. doi:10.1038/cr.2012.110; published online 24 July 2012

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