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

  1. Get@NRC: Modification of Akt1 by methylglyoxal promotes the proliferation of vascular smooth muscle cells (Opens in a new window)
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Journal titleFASEB Journal
Pages17461757; # of pages: 12
Subjectcyclin 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; article; cell proliferation; cell strain HEK293; controlled study; DNA synthesis; drug targeting; enzyme activity; enzyme phosphorylation; gene silencing; human; human cell; male; mass spectrometry; nonhuman; priority journal; protein modification; protein structure; rat; signal transduction; smooth muscle fiber; vascular smooth muscle; Animals; Blotting, Western; Cell Line; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; HEK293 Cells; Humans; Male; Mass Spectrometry; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyruvaldehyde; Rats
AbstractMethylglyoxal (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.
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AffiliationNational Research Council Canada (NRC-CNRC); NRC Plant Biotechnology Institute (PBI-IBP)
Peer reviewedYes
NPARC number21271255
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Record identifier6e37ce67-fddc-455c-ac6f-129f9484b2d1
Record created2014-03-24
Record modified2016-05-09
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