Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia
Bosutti, Alessandra (Manchester Metropolitan University)
Qi, Jie (Manchester Metropolitan University)
Pennucci, Roberta (IRCCS Ospedale San Raffaele (Milà, Itàlia))
Bolton, David (Chip-Man Technologies Ltd)
Matou, Sabine (Manchester Metropolitan University)
Ali, Kamela (Manchester Metropolitan University)
Tsai, Li-Huei (Harvard University)
Krupinski, Jerzy (Hospital Universitari MútuaTerrassa (Terrassa, Catalunya))
Petcu, Eugene B. (Griffith University)
Montaner, Joan (Hospital Universitari Vall d'Hebron)
Al Baradie, Raid (Almajmaah University)
Caccuri, Francesca (University of Brescia)
Caruso, Arnaldo (University of Brescia)
Alessandri, Giulio (Fondazione Istituto di Ricovero e Cura Carattere Scientifico Neurological Institute 'Carlo Besta')
Kumar, Shant (Manchester University (Regne Unit))
Rodríguez, Cristina (Institut d'Investigació Biomèdica Sant Pau)
Martínez-González, José (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Slevin, Mark (Griffith University (Austràlia))
Universitat Autònoma de Barcelona

Fecha:	2013
Resumen:	Cyclin-dependent kinase-5 (Cdk5) is over-expressed in both neurons and microvessels in hypoxic regions of stroke tissue and has a significant pathological role following hyper-phosphorylation leading to calpain-induced cell death. Here, we have identified a critical role of Cdk5 in cytoskeleton/focal dynamics, wherein its activator, p35, redistributes along actin microfilaments of spreading cells co-localising with p)Cdk5, talin/integrin beta-1 at the lamellipodia in polarising cells. Cdk5 inhibition (roscovitine) resulted in actin-cytoskeleton disorganisation, prevention of protein co-localization and inhibition of movement. Cells expressing Cdk5 (D144N) kinase mutant, were unable to spread, migrate and form tube-like structures or sprouts, while Cdk5 wild-type over-expression showed enhanced motility and angiogenesis in vitro, which was maintained during hypoxia. Gene microarray studies demonstrated myocyte enhancer factor (MEF2C) as a substrate for Cdk5-mediated angiogenesis in vitro. MEF2C showed nuclear co-immunoprecipitation with Cdk5 and almost complete inhibition of differentiation and sprout formation following siRNA knock-down. In hypoxia, insertion of Cdk5/p25-inhibitory peptide (CIP) vector preserved and enhanced in vitro angiogenesis. These results demonstrate the existence of critical and complementary signalling pathways through Cdk5 and p35, and through which coordination is a required factor for successful angiogenesis in sustained hypoxic condition. © 2013 Bosutti et al.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	PloS one, Vol. 8 Núm. 9 (30 2013) , p. e75538, ISSN 1932-6203

DOI: 10.1371/journal.pone.0075538
PMID: 24098701

16 p, 6.0 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut de Recerca Sant Pau
Artículos > Artículos de investigación
Artículos > Artículos publicados