IGF-1 protects against dexamethasone-induced cell death in insulin secreting INS-1 cells independent of AKT/PKB phosphorylation

被引:24
作者
Avram, Diana [1 ]
Ranta, Felicia [1 ]
Hennige, Anita M. [2 ]
Berchtold, Susanne [1 ]
Hopp, Sabine [2 ]
Haering, Hans-Ulrich [2 ]
Lang, Florian [1 ]
Ullrich, Susanne [1 ,2 ]
机构
[1] Univ Tubingen, Inst Physiol, D-72074 Tubingen, Germany
[2] Univ Tubingen Hosp, Dept Internal Med 4, Tubingen, Germany
基金
欧盟地平线“2020”;
关键词
apoptosis; proliferation; insulin secreting cells; dexamethasone; IRS-2; PI3K; PKB/Akt; ERK; phosphorylation;
D O I
10.1159/000129638
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Appropriate insulin secretion depends on beta-cell mass that is determined by the balance between cell proliferation and death. IGF-1 stimulates proliferation and protects against apoptosis. In contrast, glucocorticoids promote cell death. In this study we examined molecular interactions of the glucocorticoid dexamethasone (dexa) with IGF-1 signalling pathways in insulin secreting INS-1 cells. IGF-1 (50 ng/ml) increased the growth rate and stimulated BrdU incorporation, while dexa (100 nmol/l) inhibited cell growth, BrdU incorporation and induced apoptosis. Dexa-induced cell death was partially antagonized by IGF-1. This protection was further increased by LY294002 (10 mu mol/l), an inhibitor of PI3 kinase. In contrast, MAP kinase inhibitor PD98059 (10 mu mol/l) significantly reduced the protective effect of IGF-1. The analysis of signalling pathways by Western blotting revealed that dexa increased IRS-2 protein abundance while the expression of PI3K, PKB and ERK remained unchanged. Despite increased IRS-2 protein, IRS-2 tyrosine phosphorylation stimulated by IGF-1 was inhibited by dexa. Dexa treatment reduced basal PKB phosphorylation. However, IGF-1-mediated stimulation of PKB phosphorylation was not affected by dexa, but ERK phosphorylation was reduced. LY294002 restored IGF-1-induced ERK phosphorylation. These data suggest that dexa induces apoptosis in INS-1 cells by inhibiting phosphorylation of IRS-2, PKB and ERK. IGF-1 counteracts dexa-mediated apoptosis in the presence of reduced PKB but increased ERK phosphorylation. Copyright (C) 2008 S. Karger AG, Basel.
引用
收藏
页码:455 / 462
页数:8
相关论文
共 48 条
[1]   Mechanism of activation and function of protein kinase B [J].
Alessi, DR ;
Cohen, P .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 1998, 8 (01) :55-62
[2]   Insulin signal transduction through protein kinase cascades [J].
Avruch, J .
MOLECULAR AND CELLULAR BIOCHEMISTRY, 1998, 182 (1-2) :31-48
[3]  
Bréant B, 2006, HORM RES, V65, P98, DOI 10.1159/000091513
[4]   Differential activation mechanisms of Erk-1/2 and p70S6K by glucose in pancreatic β-cells [J].
Briaud, I ;
Lingohr, MK ;
Dickson, LM ;
Wrede, CE ;
Rhodes, CJ .
DIABETES, 2003, 52 (04) :974-983
[5]   Dexamethasone impairs insulin signalling and glucose transport by depletion of insulin receptor substrate-1, phosphatidylinositol 3-kinase and protein kinase B in primary cultured rat adipocytes [J].
Burén, J ;
Liu, HX ;
Jensen, J ;
Eriksson, JW .
EUROPEAN JOURNAL OF ENDOCRINOLOGY, 2002, 146 (03) :419-429
[6]   IRS proteins and β-cell function [J].
Burks, DJ ;
White, MF .
DIABETES, 2001, 50 :S140-S145
[7]   Pancreatic deletion of insulin receptor substrate 2 reduces beta and alpha cell mass and impairs glucose homeostasis in mice [J].
Cantley, J. ;
Choudhury, A. I. ;
Asare-Anane, H. ;
Selman, C. ;
Lingard, S. ;
Heffron, H. ;
Herrera, P. ;
Persaud, S. J. ;
Withers, D. J. .
DIABETOLOGIA, 2007, 50 (06) :1248-1256
[8]  
Chang FM, 2003, INT J ONCOL, V22, P469
[9]   Cellular survival: a play in three Akts [J].
Datta, SR ;
Brunet, A ;
Greenberg, ME .
GENES & DEVELOPMENT, 1999, 13 (22) :2905-2927
[10]   Pancreatic β-cell growth and survival in the onset of type 2 diabetes:: a role for protein kinase B in the Akt? [J].
Dickson, LM ;
Rhodes, CJ .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2004, 287 (02) :E192-E198