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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Public Library of Science
2014
|
| Online Access: | http://hdl.handle.net/1721.1/83510 https://orcid.org/0000-0003-1262-0592 |
| _version_ | 1811094923460476928 |
|---|---|
| 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 |
| author2 | Picower Institute for Learning and Memory |
| author_facet | Picower Institute for Learning and Memory 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 | MIT |
| 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[subscript (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. |
| first_indexed | 2024-09-23T16:07:40Z |
| format | Article |
| id | mit-1721.1/83510 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:07:40Z |
| publishDate | 2014 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/835102022-10-02T06:30:11Z 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 Picower Institute for Learning and Memory Tsai, Li-Huei 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[subscript (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. 2014-01-06T19:13:06Z 2014-01-06T19:13:06Z 2013-09 2013-05 Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/83510 Bosutti, Alessandra, Jie Qi, Roberta Pennucci, David Bolton, Sabine Matou, Kamela Ali, Li-Huei Tsai, et al. “Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia.” Edited by Alain-Pierre Gadeau. PLoS ONE 8, no. 9 (September 30, 2013): e75538. https://orcid.org/0000-0003-1262-0592 en_US http://dx.doi.org/10.1371/journal.pone.0075538 PLoS ONE http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | 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 |
| url | http://hdl.handle.net/1721.1/83510 https://orcid.org/0000-0003-1262-0592 |
| work_keys_str_mv | AT bosuttialessandra targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT qijie targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT pennucciroberta targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT boltondavid targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT matousabine targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT alikamela targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT tsailihuei targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT krupinskijerzy targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT petcueugeneb targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT montanerjoan targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT albaradieraid targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT caccurifrancesca targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT carusoarnaldo targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT alessandrigiulio targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT kumarshant targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT rodriguezcristina targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT martinezgonzalezjose targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia AT slevinmark targetingp35cdk5signallingviacippeptidepromotesangiogenesisinhypoxia |