Targeting p35/Cdk5 signalling via CIP-peptide promotes angiogenesis in hypoxia.
Authors
Bosutti, AQi, 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
Affiliation
School of Healthcare Science, Manchester Metropolitan University, Manchester, United Kingdom.Issue Date
2013
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Show full item recordAbstract
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 ONEJournal
PloS ONEDOI
10.1371/journal.pone.0075538PubMed ID
24098701Type
ArticleLanguage
enISSN
1932-6203ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0075538
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