title: Regulation of P21 during diabetes-associated stress of the endoplasmic reticulum.
abstract: Endoplasmic reticulum (ER) stress plays a major role in the pathogenesis of diabetes by inducing β-cell apoptosis in the islets of Langerhans. In this study, we show that the transcription factor CHOP, which is instrumental for the induction of ER-stress-associated apoptosis and the pancreatic dysfunction in diabetes, regulates the expression of P21 (WAF1), a cell cycle regulator with anti-apoptotic activity that promotes cell survival. Deficiency of P21 sensitizes pancreatic β-cells to glucotoxicity, while in mice genetic ablation of P21 accelerates experimental diet-induced diabetes, results indicative of a protective role for P21 in the development of the disease. Conversely, pharmacological stimulation of P21 expression by nutlin-3a, an inhibitor of P53-MDM2 interaction, restores pancreatic function and facilitates glucose homeostasis. These findings indicate that P21 acts as an inhibitor of ER-stress-associated tissue damage and that stimulation of P21 activity can be beneficial for the management of diabetes and probably of other conditions in which ER-stress-associated death is undesirable.
authors: Department of Biological ChemistryUniversity of Athens Medical School, Athens 11527, GreeceDepartment of Basic SciencesDental School, University of Athens, Athens 11527, GreeceDepartment of PathologyMicrobiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USADepartment of Drug Discovery and Biomedical SciencesUniversity of South Carolina, Columbia, South Carolina 29425, USA.
authors: Chrysovalantou
authors: C
authors: Mihailidou
authors: Department of Biological ChemistryUniversity of Athens Medical School, Athens 11527, GreeceDepartment of Basic SciencesDental School, University of Athens, Athens 11527, GreeceDepartment of PathologyMicrobiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USADepartment of Drug Discovery and Biomedical SciencesUniversity of South Carolina, Columbia, South Carolina 29425, USA Department of Biological ChemistryUniversity of Athens Medical School, Athens 11527, GreeceDepartment of Basic SciencesDental School, University of Athens, Athens 11527, GreeceDepartment of PathologyMicrobiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USADepartment of Drug Discovery and Biomedical SciencesUniversity of South Carolina, Columbia, South Carolina 29425, USA.
authors: Ioulia
authors: I
authors: Chatzistamou
authors: Department of Biological ChemistryUniversity of Athens Medical School, Athens 11527, GreeceDepartment of Basic SciencesDental School, University of Athens, Athens 11527, GreeceDepartment of PathologyMicrobiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USADepartment of Drug Discovery and Biomedical SciencesUniversity of South Carolina, Columbia, South Carolina 29425, USA.
authors: Athanasios G
authors: AG
authors: Papavassiliou
authors: Department of Biological ChemistryUniversity of Athens Medical School, Athens 11527, GreeceDepartment of Basic SciencesDental School, University of Athens, Athens 11527, GreeceDepartment of PathologyMicrobiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USADepartment of Drug Discovery and Biomedical SciencesUniversity of South Carolina, Columbia, South Carolina 29425, USA Department of Biological ChemistryUniversity of Athens Medical School, Athens 11527, GreeceDepartment of Basic SciencesDental School, University of Athens, Athens 11527, GreeceDepartment of PathologyMicrobiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USADepartment of Drug Discovery and Biomedical SciencesUniversity of South Carolina, Columbia, South Carolina 29425, USA kiarish@sccp.sc.edu.
authors: Hippokratis
authors: H
authors: Kiaris
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002460:Cell Line; D006224:Cricetinae; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D059305:Diet, High-Fat; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000378:metabolism; D013395:Sucrose / Q000008:administration & dosage; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C539791:Bax-inhibiting peptide, BIP; D001786:Blood Glucose; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D009842:Oligopeptides; C018551:glucose-regulated proteins; D051742:Transcription Factor CHOP; D013395:Sucrose
keywords: chaperone; glucose; glucotoxicity; unfolded protein response; β cells