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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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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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. |
format | Online Article Text |
id | pubmed-3787057 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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