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Modification of Akt1 by methylglyoxal promotes the proliferation of vascular smooth muscle cells

Par Conseil national de recherches du Canada

DOITrouver le DOI : https://doi.org/10.1096/fj.10-178053
AuteurRechercher : ; Rechercher : ; Rechercher : 1; Rechercher : ; Rechercher : ; Rechercher :
Affiliation
  1. Conseil national de recherches du Canada. Institut de biotechnologie des plantes du CNRC
FormatTexte, Article
Sujetcyclin dependent kinase 2; cysteine derivative; glycogen synthase kinase 3alpha; glycogen synthase kinase 3beta; methylglyoxal; protein kinase B; protein kinase B inhibitor; protein p21; protein serine threonine kinase; serine derivative; sh 6; threonine; unclassified drug; animal cell; animal experiment; animal model; animal tissue; cell proliferation; cell strain HEK293; DNA synthesis; drug targeting; enzyme activity; enzyme phosphorylation; gene silencing; human cell; male; mass spectrometry; protein modification; protein structure; rat; signal transduction; smooth muscle fiber; vascular smooth muscle; Blotting, Western; Cell Line; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; HEK293 Cells; Male; Mass Spectrometry; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyruvaldehyde; Rats
Résumé
Methylglyoxal (MG), a reactive dicarbonyl molecule, can modify protein to form advanced glycation endproducts. Increased MG level has been implicated in proliferative vascular diseases, but the underlying mechanisms are not clear yet. The serine/threonine kinase, Akt, regulates multiple signaling pathways that control cell proliferation. Using mass spectrometric analysis, we have detected the modification of Akt1 by MG at Cys 77. This structural modification increased Akt1 phosphorylation at Ser 473 and Thr 308. Akt1 phosphorylation and activity were also increased by MG treatment (<50 μM) in cultured vascular smooth muscle cells (VSMCs). MG treatment of VSMCs led to increased DNA synthesis (EC 50=5.8 μM), cell proliferation, phosphorylation of p21 and glycogen synthase kinase-3α/β (GSK-3α/β), and increased cyclin-dependent kinase 2 (CDK2) activity. These effects of MG were significantly inhibited by silencing Akt1 or by an Akt inhibitor. Overexpression of Akt1 Cys 77Ser mutant in HEK-293 cells increased cell proliferation and DNA synthesis, concurrent with an increase in Akt1 activity, which could not be further augmented by MG treatment. It is concluded that MG-induced VSMC proliferation is mediated by the activation of Akt1 via the modification of Akt1 at Cys 77. © FASEB.
Date de publication
Dans
  • FASEB Journal 25, nº 5 (2011) : 1746–1757.
Langueanglais
Publications évaluées par des pairsOui
Numéro NPARC21271255
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Identificateur de l’enregistrement6e37ce67-fddc-455c-ac6f-129f9484b2d1
Enregistrement créé2014-03-24
Enregistrement modifié2020-04-21
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