Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia

Autor: Jerzy Krupinski, Mark Slevin, Shant Kumar, Alessandra Bosutti, Arnaldo Caruso, Roberta Pennucci, Cristina Rodríguez, Giulio Alessandri, Raid Al Baradie, Kamela Ali, Li-Huei Tsai, Sabine Matou, David A. E. Bolton, Francesca Caccuri, Jie Qi, Joan Montaner, José Martínez-González, Eugen Bogdan Petcu
Přispěvatelé: Picower Institute for Learning and Memory, Tsai, Li-Huei, Bosutti, Alessandra, Qi, J, Pennucci, R, Bolton, D, Matou, S, Ali, K, Tsai, Lh, Krupinski, J, Petcu, Eb, Montaner, J, Al Baradie, R, Caccuri, F, Caruso, A, Alessandri, G, Kumar, S, Rodriguez, C, Martinez Gonzalez, J, Slevin, M.
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Angiogenesis
lcsh:Medicine
Cell Cycle Proteins
Neovascularization
0302 clinical medicine
Cell Movement
Pseudopodia
lcsh:Science
Hypoxia
Cytoskeleton
0303 health sciences
Multidisciplinary
biology
MEF2 Transcription Factors
Cell migration
Cell biology
Stroke
Actin Cytoskeleton
Colorimetry
RNA Interference
Lamellipodium
medicine.symptom
Research Article
Signal Transduction
Integrin
Blotting
Western
Mutation
Missense
Neovascularization
Physiologic
Cell Line
03 medical and health sciences
medicine
Roscovitine
Humans
Immunoprecipitation
030304 developmental biology
Adaptor Proteins
Signal Transducing
DNA Primers
Analysis of Variance
Cyclin-dependent kinase 5
lcsh:R
Cyclin-Dependent Kinase 5
Actin cytoskeleton
Microarray Analysis
Microscopy
Fluorescence
nervous system
Purines
biology.protein
lcsh:Q
Peptides
030217 neurology & neurosurgery
Zdroj: PLoS
PLoS ONE
PLoS ONE, Vol 8, Iss 9, p e75538 (2013)
PLoS One
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname
ISSN: 1932-6203
Popis: 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(Tyr15)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.
Databáze: OpenAIRE
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