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dc.contributor.advisor Casey, Patrick J en_US
dc.contributor.author Doughty-Shenton, D
dc.contributor.author Joseph, JD
dc.contributor.author Zhang, J
dc.contributor.author Pagliarini, DJ
dc.contributor.author Kim, Y
dc.contributor.author Lu, D
dc.contributor.author Dixon, JE
dc.contributor.author Casey, PJ
dc.coverage.spatial United States
dc.date.accessioned 2009-08-27T18:21:30Z
dc.date.issued 2010-05
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/20167843
dc.identifier jpet.109.163329
dc.identifier.citation J Pharmacol Exp Ther, 2010, 333 (2), pp. 584 - 592
dc.identifier.uri http://hdl.handle.net/10161/1303
dc.description Dissertation en_US
dc.description.abstract The dual-specificity protein tyrosine phosphatases (PTPs) play integral roles in the regulation of cell signaling. There is a need for new tools to study these phosphatases, and the identification of inhibitors potentially affords not only new means for their study, but also possible therapeutics for the treatment of diseases caused by their dysregulation. However, the identification of selective inhibitors of the protein phosphatases has proven somewhat difficult. PTP localized to mitochondrion 1 (PTPMT1) is a recently discovered dual-specificity phosphatase that has been implicated in the regulation of insulin secretion. Screening of a commercially available small-molecule library yielded alexidine dihydrochloride, a dibiguanide compound, as an effective and selective inhibitor of PTPMT1 with an in vitro concentration that inhibits response by 50% of 1.08 microM. A related dibiguanide analog, chlorhexidine dihydrochloride, also significantly inhibited PTPMT1, albeit with lower potency, while a monobiguanide analog showed very weak inhibition. Treatment of isolated rat pancreatic islets with alexidine dihydrochloride resulted in a dose-dependent increase in insulin secretion, whereas treatment of a pancreatic beta-cell line with the drug affected the phosphorylation of mitochondrial proteins in a manner similar to genetic inhibition of PTPMT1. Furthermore, knockdown of PTPMT1 in rat islets rendered them insensitive to alexidine dihydrochloride treatment, providing evidence for mechanism-based activity of the inhibitor. Taken together, these studies establish alexidine dihydrochloride as an effective inhibitor of PTPMT1, both in vitro and in cells, and support the notion that PTPMT1 could serve as a pharmacological target in the treatment of type II diabetes.
dc.format.extent 584 - 592
dc.format.mimetype application/pdf
dc.language eng
dc.language.iso en_US
dc.relation.ispartof J Pharmacol Exp Ther
dc.relation.isversionof 10.1124/jpet.109.163329
dc.subject Animals
dc.subject Biguanides
dc.subject Dose-Response Relationship, Drug
dc.subject Dual Specificity Phosphatase 1
dc.subject Immunoblotting
dc.subject Insulin
dc.subject Islets of Langerhans
dc.subject Mitochondria
dc.subject Mitochondrial Proteins
dc.subject Phosphorylation
dc.subject Rats
dc.subject Rats, Wistar
dc.title Pharmacological targeting of the mitochondrial phosphatase PTPMT1.
dc.type Journal Article
dc.department Biochemistry en_US
duke.embargo.months 12 en_US
dc.date.accessible 2010-05-18T05:00:13Z
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/20167843
pubs.issue 2
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Biochemistry
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Pharmacology & Cancer Biology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.publication-status Published
pubs.volume 333
dc.identifier.eissn 1521-0103

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