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    Targeting p35/Cdk5 signalling via CIP-peptide promotes angiogenesis in hypoxia.

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    Authors
    Bosutti, A
    Qi, J
    Pennucci, R
    Bolton, D
    Matou, S
    Ali, K
    Tsai, L-H
    Krupinski, J
    Petcu, E
    Montaner, J
    Al Baradie, R
    Caccuri, F
    Caruso, A
    Alessandri, G
    Kumar, Shant
    Rodriguez, C
    Martinez-Gonzalez, J
    Slevin, M
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    Affiliation
    School of Healthcare Science, Manchester Metropolitan University, Manchester, United Kingdom.
    Issue Date
    2013
    
    Metadata
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    Abstract
    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.
    Citation
    Targeting p35/Cdk5 signalling via CIP-peptide promotes angiogenesis in hypoxia. 2013, 8 (9):e75538 PLoS ONE
    Journal
    PloS ONE
    URI
    http://hdl.handle.net/10541/308805
    DOI
    10.1371/journal.pone.0075538
    PubMed ID
    24098701
    Type
    Article
    Language
    en
    ISSN
    1932-6203
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pone.0075538
    Scopus Count
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