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

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/foca...

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Autores principales: Bosutti, Alessandra, Qi, Jie, Pennucci, Roberta, Bolton, David, Matou, Sabine, Ali, Kamela, Tsai, Li-Huei, Krupinski, Jerzy, Petcu, Eugene B., Montaner, Joan, Al Baradie, Raid, Caccuri, Francesca, Caruso, Arnaldo, Alessandri, Giulio, Kumar, Shant, Rodriguez, Cristina, Martinez-Gonzalez, Jose, Slevin, Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787057/
https://www.ncbi.nlm.nih.gov/pubmed/24098701
http://dx.doi.org/10.1371/journal.pone.0075538
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author Bosutti, Alessandra
Qi, Jie
Pennucci, Roberta
Bolton, David
Matou, Sabine
Ali, Kamela
Tsai, Li-Huei
Krupinski, Jerzy
Petcu, Eugene B.
Montaner, Joan
Al Baradie, Raid
Caccuri, Francesca
Caruso, Arnaldo
Alessandri, Giulio
Kumar, Shant
Rodriguez, Cristina
Martinez-Gonzalez, Jose
Slevin, Mark
author_facet Bosutti, Alessandra
Qi, Jie
Pennucci, Roberta
Bolton, David
Matou, Sabine
Ali, Kamela
Tsai, Li-Huei
Krupinski, Jerzy
Petcu, Eugene B.
Montaner, Joan
Al Baradie, Raid
Caccuri, Francesca
Caruso, Arnaldo
Alessandri, Giulio
Kumar, Shant
Rodriguez, Cristina
Martinez-Gonzalez, Jose
Slevin, Mark
author_sort Bosutti, Alessandra
collection PubMed
description 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.
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spelling pubmed-37870572013-10-04 Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia Bosutti, Alessandra Qi, Jie Pennucci, Roberta Bolton, David Matou, Sabine Ali, Kamela Tsai, Li-Huei Krupinski, Jerzy Petcu, Eugene B. Montaner, Joan Al Baradie, Raid Caccuri, Francesca Caruso, Arnaldo Alessandri, Giulio Kumar, Shant Rodriguez, Cristina Martinez-Gonzalez, Jose Slevin, Mark PLoS One Research Article 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. Public Library of Science 2013-09-30 /pmc/articles/PMC3787057/ /pubmed/24098701 http://dx.doi.org/10.1371/journal.pone.0075538 Text en © 2013 Bosutti et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bosutti, Alessandra
Qi, Jie
Pennucci, Roberta
Bolton, David
Matou, Sabine
Ali, Kamela
Tsai, Li-Huei
Krupinski, Jerzy
Petcu, Eugene B.
Montaner, Joan
Al Baradie, Raid
Caccuri, Francesca
Caruso, Arnaldo
Alessandri, Giulio
Kumar, Shant
Rodriguez, Cristina
Martinez-Gonzalez, Jose
Slevin, Mark
Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia
title Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia
title_full Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia
title_fullStr Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia
title_full_unstemmed Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia
title_short Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia
title_sort targeting p35/cdk5 signalling via cip-peptide promotes angiogenesis in hypoxia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787057/
https://www.ncbi.nlm.nih.gov/pubmed/24098701
http://dx.doi.org/10.1371/journal.pone.0075538
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