{"id":{"repo_id":"strathclyde","oai_identifier":"oai:strathclyde:r494vk23n"},"canonical_url":"https://search.dev.ndltd.org/etd/strathclyde/oai:strathclyde:r494vk23n","repository":{"repo_id":"strathclyde","name":"University of Strathclyde","base_url":"https://stax.strath.ac.uk/catalog/oai"},"display":{"title":"MAP kinase phosphatase-2 in vascular smooth cell muscle function","abstract":"The progression of major cardiovascular disorders are a consequence of a pathophysiological modification within the blood vessel; a process often driven by vascular smooth muscle cell hyperproliferation. A major mechanism by which smooth muscle cell proliferation occurs involves ligand-induced activation of MAP kinase signalling (Schad et al., 2011). MAP kinases have been noteworthy but troublesome targets in cardiovascular therapeutics; thus exploration of targeting endogenous regulatory dual specificity proteins namely MAP kinase phosphatases has been advancing in recent years. Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear phosphatase with the ability to dephosphorylate and ultimately inactivate MAP kinases ERK and JNK in vitro (Lawan et al., 2012). Therefore, by the use of a novel MKP-2-/- mouse, we assess a role for MKP-2 in smooth muscle proliferation as a potential future therapeutic target in cardiovascular disease. Contrary to current literature, mouse aortic smooth muscle cells cultured from a novel Dusp4 knockout mouse exhibit no significant difference in MAP kinase signalling profiles when compared with wild-type. Interestingly however, a significant reduction in proliferation rate corresponded with MKP-2 knockout cells and further cell cycle investigation elucidated a significant accumulation of MKP-2-/- cells in G2/M phase of the cell cycle. With levels of p-cdc-2 comparable between MKP-2 wild-type and knockout cells, mitotic entry was unaffected by MKP-2 deficiency which therefore diverted our study downstream to cytokinesis. Utilising time-lapse microscopy, smooth muscle cells lacking in MKP-2 exhibited a delay in cytokinesis and failure in abscission, resulting in the dividing cells connected by an intercellular bridge. The molecular mechanism of cytokinesis requires phosphorylation of the mitotic kinase aurora B for successful division of two daughter cells. However nocodazole-arrest studies reveal MKP-2 is required for aurora B phosphorylation and its downstream target histone H3, thus identifying MKP-2 as essential in the effective completion of cytokinesis. Within this thesis, an early investigation into the possible use of Adv.WT-MKP-2 as a vascular therapeutic in human aortic smooth muscle cells (HASMCs) was conducted. The over-expression of MKP-2 negated ERK signalling and consequently resulted in a reduction in cellular proliferation. Furthermore, the reduction in cellular proliferation was shown to be caused by a G1/S accumulation in the cell cycle. Collectively, these data suggest a novel role for MKP-2 in mouse aortic smooth muscle cell proliferation, providing new insights into the understanding of MKP-2 in the completion of cytokinesis. Furthermore, MKP-2 kinase binding domain is required for successful completion of cytokinesis but may not involve the inactivation of ERK or JNK. Therefore, modification of MKP-2 expression or function may represent a new approach in reducing SMC hyperproliferation in vascular disease states.","abstract_html":"The progression of major cardiovascular disorders are a consequence of a pathophysiological modification within the blood vessel; a process often driven by vascular smooth muscle cell hyperproliferation. A major mechanism by which smooth muscle cell proliferation occurs involves ligand-induced activation of MAP kinase signalling (Schad et al., 2011). MAP kinases have been noteworthy but troublesome targets in cardiovascular therapeutics; thus exploration of targeting endogenous regulatory dual specificity proteins namely MAP kinase phosphatases has been advancing in recent years. Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear phosphatase with the ability to dephosphorylate and ultimately inactivate MAP kinases ERK and JNK in vitro (Lawan et al., 2012). Therefore, by the use of a novel MKP-2-/- mouse, we assess a role for MKP-2 in smooth muscle proliferation as a potential future therapeutic target in cardiovascular disease. Contrary to current literature, mouse aortic smooth muscle cells cultured from a novel Dusp4 knockout mouse exhibit no significant difference in MAP kinase signalling profiles when compared with wild-type. Interestingly however, a significant reduction in proliferation rate corresponded with MKP-2 knockout cells and further cell cycle investigation elucidated a significant accumulation of MKP-2-/- cells in G2/M phase of the cell cycle. With levels of p-cdc-2 comparable between MKP-2 wild-type and knockout cells, mitotic entry was unaffected by MKP-2 deficiency which therefore diverted our study downstream to cytokinesis. Utilising time-lapse microscopy, smooth muscle cells lacking in MKP-2 exhibited a delay in cytokinesis and failure in abscission, resulting in the dividing cells connected by an intercellular bridge. The molecular mechanism of cytokinesis requires phosphorylation of the mitotic kinase aurora B for successful division of two daughter cells. However nocodazole-arrest studies reveal MKP-2 is required for aurora B phosphorylation and its downstream target histone H3, thus identifying MKP-2 as essential in the effective completion of cytokinesis. Within this thesis, an early investigation into the possible use of Adv.WT-MKP-2 as a vascular therapeutic in human aortic smooth muscle cells (HASMCs) was conducted. The over-expression of MKP-2 negated ERK signalling and consequently resulted in a reduction in cellular proliferation. Furthermore, the reduction in cellular proliferation was shown to be caused by a G1/S accumulation in the cell cycle. Collectively, these data suggest a novel role for MKP-2 in mouse aortic smooth muscle cell proliferation, providing new insights into the understanding of MKP-2 in the completion of cytokinesis. Furthermore, MKP-2 kinase binding domain is required for successful completion of cytokinesis but may not involve the inactivation of ERK or JNK. Therefore, modification of MKP-2 expression or function may represent a new approach in reducing SMC hyperproliferation in vascular disease states.","abstract_has_math":false,"creators":["Torrance, Emma"],"institution":"University of Strathclyde","degree_name":"phd","degree_level":"doctoral-pg","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013","date_published":"2013","updated_at":"2026-07-24T04:46:34Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.48730/y7gq-pj71"],"render_values":[{"text":"10.48730/y7gq-pj71","href":"https://doi.org/10.48730/y7gq-pj71","code":true}]},{"key":"dc:identifier","label":"Identifier","values":["T13743"],"render_values":[{"text":"T13743","href":null,"code":true}]}]},"links":{"outbound_url":"https://stax.strath.ac.uk/concern/theses/r494vk23n","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Torrance, Emma"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2013"]},{"key":"dc:date.issued","label":"Date","values":["2013"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Strathclyde Institute of Pharmacy and Biomedical Sciences"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Strathclyde"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["doctoral-pg"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["phd"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["T13743"]},{"key":"dc:identifier.doi","label":"DOI","values":["10.48730/y7gq-pj71"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://stax.strath.ac.uk/concern/theses/r494vk23n"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The progression of major cardiovascular disorders are a consequence of a pathophysiological modification within the blood vessel; a process often driven by vascular smooth muscle cell hyperproliferation. A major mechanism by which smooth muscle cell proliferation occurs involves ligand-induced activation of MAP kinase signalling (Schad et al., 2011). MAP kinases have been noteworthy but troublesome targets in cardiovascular therapeutics; thus exploration of targeting endogenous regulatory dual specificity proteins namely MAP kinase phosphatases has been advancing in recent years. Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear phosphatase with the ability to dephosphorylate and ultimately inactivate MAP kinases ERK and JNK in vitro (Lawan et al., 2012). Therefore, by the use of a novel MKP-2-/- mouse, we assess a role for MKP-2 in smooth muscle proliferation as a potential future therapeutic target in cardiovascular disease. Contrary to current literature, mouse aortic smooth muscle cells cultured from a novel Dusp4 knockout mouse exhibit no significant difference in MAP kinase signalling profiles when compared with wild-type. Interestingly however, a significant reduction in proliferation rate corresponded with MKP-2 knockout cells and further cell cycle investigation elucidated a significant accumulation of MKP-2-/- cells in G2/M phase of the cell cycle. With levels of p-cdc-2 comparable between MKP-2 wild-type and knockout cells, mitotic entry was unaffected by MKP-2 deficiency which therefore diverted our study downstream to cytokinesis. Utilising time-lapse microscopy, smooth muscle cells lacking in MKP-2 exhibited a delay in cytokinesis and failure in abscission, resulting in the dividing cells connected by an intercellular bridge. The molecular mechanism of cytokinesis requires phosphorylation of the mitotic kinase aurora B for successful division of two daughter cells. However nocodazole-arrest studies reveal MKP-2 is required for aurora B phosphorylation and its downstream target histone H3, thus identifying MKP-2 as essential in the effective completion of cytokinesis. Within this thesis, an early investigation into the possible use of Adv.WT-MKP-2 as a vascular therapeutic in human aortic smooth muscle cells (HASMCs) was conducted. The over-expression of MKP-2 negated ERK signalling and consequently resulted in a reduction in cellular proliferation. Furthermore, the reduction in cellular proliferation was shown to be caused by a G1/S accumulation in the cell cycle. Collectively, these data suggest a novel role for MKP-2 in mouse aortic smooth muscle cell proliferation, providing new insights into the understanding of MKP-2 in the completion of cytokinesis. Furthermore, MKP-2 kinase binding domain is required for successful completion of cytokinesis but may not involve the inactivation of ERK or JNK. Therefore, modification of MKP-2 expression or function may represent a new approach in reducing SMC hyperproliferation in vascular disease states."]},{"key":"dc:description.abstract","label":"Abstract","values":["The progression of major cardiovascular disorders are a consequence of a pathophysiological modification within the blood vessel; a process often driven by vascular smooth muscle cell hyperproliferation. A major mechanism by which smooth muscle cell proliferation occurs involves ligand-induced activation of MAP kinase signalling (Schad et al., 2011). MAP kinases have been noteworthy but troublesome targets in cardiovascular therapeutics; thus exploration of targeting endogenous regulatory dual specificity proteins namely MAP kinase phosphatases has been advancing in recent years. Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear phosphatase with the ability to dephosphorylate and ultimately inactivate MAP kinases ERK and JNK in vitro (Lawan et al., 2012). Therefore, by the use of a novel MKP-2-/- mouse, we assess a role for MKP-2 in smooth muscle proliferation as a potential future therapeutic target in cardiovascular disease. Contrary to current literature, mouse aortic smooth muscle cells cultured from a novel Dusp4 knockout mouse exhibit no significant difference in MAP kinase signalling profiles when compared with wild-type. Interestingly however, a significant reduction in proliferation rate corresponded with MKP-2 knockout cells and further cell cycle investigation elucidated a significant accumulation of MKP-2-/- cells in G2/M phase of the cell cycle. With levels of p-cdc-2 comparable between MKP-2 wild-type and knockout cells, mitotic entry was unaffected by MKP-2 deficiency which therefore diverted our study downstream to cytokinesis. Utilising time-lapse microscopy, smooth muscle cells lacking in MKP-2 exhibited a delay in cytokinesis and failure in abscission, resulting in the dividing cells connected by an intercellular bridge. The molecular mechanism of cytokinesis requires phosphorylation of the mitotic kinase aurora B for successful division of two daughter cells. However nocodazole-arrest studies reveal MKP-2 is required for aurora B phosphorylation and its downstream target histone H3, thus identifying MKP-2 as essential in the effective completion of cytokinesis. Within this thesis, an early investigation into the possible use of Adv.WT-MKP-2 as a vascular therapeutic in human aortic smooth muscle cells (HASMCs) was conducted. The over-expression of MKP-2 negated ERK signalling and consequently resulted in a reduction in cellular proliferation. Furthermore, the reduction in cellular proliferation was shown to be caused by a G1/S accumulation in the cell cycle. Collectively, these data suggest a novel role for MKP-2 in mouse aortic smooth muscle cell proliferation, providing new insights into the understanding of MKP-2 in the completion of cytokinesis. Furthermore, MKP-2 kinase binding domain is required for successful completion of cytokinesis but may not involve the inactivation of ERK or JNK. Therefore, modification of MKP-2 expression or function may represent a new approach in reducing SMC hyperproliferation in vascular disease states."]},{"key":"dc:title","label":"Title","values":["MAP kinase phosphatase-2 in vascular smooth cell muscle function"]}]}],"canonical_facts":{"dc:creator":["Torrance, Emma"],"dc:date":["2013"],"dc:date.issued":["2013"],"dc:description":["The progression of major cardiovascular disorders are a consequence of a pathophysiological modification within the blood vessel; a process often driven by vascular smooth muscle cell hyperproliferation. A major mechanism by which smooth muscle cell proliferation occurs involves ligand-induced activation of MAP kinase signalling (Schad et al., 2011). MAP kinases have been noteworthy but troublesome targets in cardiovascular therapeutics; thus exploration of targeting endogenous regulatory dual specificity proteins namely MAP kinase phosphatases has been advancing in recent years. Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear phosphatase with the ability to dephosphorylate and ultimately inactivate MAP kinases ERK and JNK in vitro (Lawan et al., 2012). Therefore, by the use of a novel MKP-2-/- mouse, we assess a role for MKP-2 in smooth muscle proliferation as a potential future therapeutic target in cardiovascular disease. Contrary to current literature, mouse aortic smooth muscle cells cultured from a novel Dusp4 knockout mouse exhibit no significant difference in MAP kinase signalling profiles when compared with wild-type. Interestingly however, a significant reduction in proliferation rate corresponded with MKP-2 knockout cells and further cell cycle investigation elucidated a significant accumulation of MKP-2-/- cells in G2/M phase of the cell cycle. With levels of p-cdc-2 comparable between MKP-2 wild-type and knockout cells, mitotic entry was unaffected by MKP-2 deficiency which therefore diverted our study downstream to cytokinesis. Utilising time-lapse microscopy, smooth muscle cells lacking in MKP-2 exhibited a delay in cytokinesis and failure in abscission, resulting in the dividing cells connected by an intercellular bridge. The molecular mechanism of cytokinesis requires phosphorylation of the mitotic kinase aurora B for successful division of two daughter cells. However nocodazole-arrest studies reveal MKP-2 is required for aurora B phosphorylation and its downstream target histone H3, thus identifying MKP-2 as essential in the effective completion of cytokinesis. Within this thesis, an early investigation into the possible use of Adv.WT-MKP-2 as a vascular therapeutic in human aortic smooth muscle cells (HASMCs) was conducted. The over-expression of MKP-2 negated ERK signalling and consequently resulted in a reduction in cellular proliferation. Furthermore, the reduction in cellular proliferation was shown to be caused by a G1/S accumulation in the cell cycle. Collectively, these data suggest a novel role for MKP-2 in mouse aortic smooth muscle cell proliferation, providing new insights into the understanding of MKP-2 in the completion of cytokinesis. Furthermore, MKP-2 kinase binding domain is required for successful completion of cytokinesis but may not involve the inactivation of ERK or JNK. Therefore, modification of MKP-2 expression or function may represent a new approach in reducing SMC hyperproliferation in vascular disease states."],"dc:description.abstract":["The progression of major cardiovascular disorders are a consequence of a pathophysiological modification within the blood vessel; a process often driven by vascular smooth muscle cell hyperproliferation. A major mechanism by which smooth muscle cell proliferation occurs involves ligand-induced activation of MAP kinase signalling (Schad et al., 2011). MAP kinases have been noteworthy but troublesome targets in cardiovascular therapeutics; thus exploration of targeting endogenous regulatory dual specificity proteins namely MAP kinase phosphatases has been advancing in recent years. Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear phosphatase with the ability to dephosphorylate and ultimately inactivate MAP kinases ERK and JNK in vitro (Lawan et al., 2012). Therefore, by the use of a novel MKP-2-/- mouse, we assess a role for MKP-2 in smooth muscle proliferation as a potential future therapeutic target in cardiovascular disease. Contrary to current literature, mouse aortic smooth muscle cells cultured from a novel Dusp4 knockout mouse exhibit no significant difference in MAP kinase signalling profiles when compared with wild-type. Interestingly however, a significant reduction in proliferation rate corresponded with MKP-2 knockout cells and further cell cycle investigation elucidated a significant accumulation of MKP-2-/- cells in G2/M phase of the cell cycle. With levels of p-cdc-2 comparable between MKP-2 wild-type and knockout cells, mitotic entry was unaffected by MKP-2 deficiency which therefore diverted our study downstream to cytokinesis. Utilising time-lapse microscopy, smooth muscle cells lacking in MKP-2 exhibited a delay in cytokinesis and failure in abscission, resulting in the dividing cells connected by an intercellular bridge. The molecular mechanism of cytokinesis requires phosphorylation of the mitotic kinase aurora B for successful division of two daughter cells. However nocodazole-arrest studies reveal MKP-2 is required for aurora B phosphorylation and its downstream target histone H3, thus identifying MKP-2 as essential in the effective completion of cytokinesis. Within this thesis, an early investigation into the possible use of Adv.WT-MKP-2 as a vascular therapeutic in human aortic smooth muscle cells (HASMCs) was conducted. The over-expression of MKP-2 negated ERK signalling and consequently resulted in a reduction in cellular proliferation. Furthermore, the reduction in cellular proliferation was shown to be caused by a G1/S accumulation in the cell cycle. Collectively, these data suggest a novel role for MKP-2 in mouse aortic smooth muscle cell proliferation, providing new insights into the understanding of MKP-2 in the completion of cytokinesis. Furthermore, MKP-2 kinase binding domain is required for successful completion of cytokinesis but may not involve the inactivation of ERK or JNK. Therefore, modification of MKP-2 expression or function may represent a new approach in reducing SMC hyperproliferation in vascular disease states."],"dc:identifier":["T13743"],"dc:identifier.doi":["10.48730/y7gq-pj71"],"dc:identifier.uri":["https://stax.strath.ac.uk/concern/theses/r494vk23n"],"dc:publisher.department":["Strathclyde Institute of Pharmacy and Biomedical Sciences"],"dc:publisher.institution":["University of Strathclyde"],"dc:title":["MAP kinase phosphatase-2 in vascular smooth cell muscle function"],"dc:type.qualificationlevel":["doctoral-pg"],"dc:type.qualificationname":["phd"]},"updated_at":"2026-07-24T04:46:34Z"}