title: Exposure to chronic hyperglycemic conditions results in Ras-related C3 botulinum toxin substrate 1 (Rac1)-mediated activation of p53 and ATM kinase in pancreatic β-cells.
abstract: Chronic hyperglycemia (HG) promotes pancreatic islet dysfunction which leads to the onset of T2DM. This study is aimed at defining regulatory roles of Rac1, a small G-protein, in the activation of p53 and ATM kinase in pancreatic β-cells, under the duress of HG conditions. We report significant stimulatory effects of HG (20 mM; 24 h) on p53 activation in INS-1 832/13 cells, normal rodent and human islets. Pharmacological inhibition of Rac1 (EHT1864 or NSC23766) significantly suppressed HG-induced p53 activation in INS-1 832/13 cells and rat islets, suggesting novel roles for this small G-protein in the activation of p53. Inhibition of Rac1 geranylgeranylation with simvastatin or GGTI-2147, significantly attenuated HG-induced p53 activation, suggesting requisite roles for this signaling step in HG-mediated effects on β-cells. HG-induced p53 activation was also suppressed by SB203580, a known inhibitor of p38MAPK. Additionally, we observed increased activation of ATM kinase under HG conditions, which was blocked in presence of EHT1864. Furthermore, pharmacological inhibition of ATM kinase (KU55933) reduced activation of ATM kinase, but not p53, suggesting that HG-mediated activation of p53 and ATM could represent independent pro-apoptotic events. In conclusion, these data indicate that sustained activation of Rac1-p38MAPK signaling axis leads to activation of p53 leading to β-cell dysfunction under the duress of chronic hyperglycemic conditions.
authors.affiliation: Beta-Cell Biochemistry Laboratory, John D. Dingell VA Medical Center, B-4237 Research Service, 4646 John R, Detroit, MI, 48201, USA.|Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, 48201, USA.|Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Brehm Diabetes Research Center, University of Michigan Medical School, Ann Arbor, MI, 48105-1912, USA.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Sidarala
authors.affiliation: Beta-Cell Biochemistry Laboratory, John D. Dingell VA Medical Center, B-4237 Research Service, 4646 John R, Detroit, MI, 48201, USA. akowluru@med.wayne.edu.|Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, 48201, USA. akowluru@med.wayne.edu.
authors.forename: Anjaneyulu
authors.initials: A
authors.lastname: Kowluru
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007093:Imidazoles / Q000008:administration & dosage; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology; D009025:Morpholines / Q000008:administration & dosage; D054876:Prenylation / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage; D011753:Pyrones / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage; D051381:Rats; D019821:Simvastatin / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; C506907:EHT 1864; D007093:Imidazoles; D007328:Insulin; D009025:Morpholines; D011725:Pyridines; D011753:Pyrones; D011804:Quinolines; D016159:Tumor Suppressor Protein p53; D019821:Simvastatin; D064007:Ataxia Telangiectasia Mutated Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; C093642:SB 203580
keywords: ATM kinase; Glucotoxicity; Pancreatic islet; Rac1; p38MAPK; p53