MicroRNA-7 Regulates the mTOR Pathway and Proliferation in Adult Pancreatic β-Cells

被引:154
作者
Wang, You [1 ,2 ]
Liu, Jiangying [1 ,2 ]
Liu, Chengyang [3 ]
Naji, Ali [3 ]
Stoffers, Doris A. [1 ,2 ]
机构
[1] Univ Penn, Dept Med, Perelman Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA
[2] Univ Penn, Inst Diabet Obes & Metab, Perelman Sch Med, Philadelphia, PA 19104 USA
[3] Univ Penn, Dept Surg, Perelman Sch Med, Div Transplant Surg, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院;
关键词
GROWTH-FACTOR RECEPTOR; INSULIN-RESISTANCE; SIGNALING PATHWAY; IN-VIVO; EXPRESSION; MASS; MICE; AKT; PHOSPHORYLATION; TURNOVER;
D O I
10.2337/db12-0451
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Elucidating the mechanism underlying the poor proliferative capacity of adult pancreatic beta-cells is critical to regenerative therapeutic approaches for diabetes. Here, we show that the microRNA (miR)-7/7ab family member miR-7a is enriched in mouse adult pancreatic islets compared with miR-7b. Remarkably, miR-7a targets five components of the mTOR signaling pathway. Further, inhibition of miR-7a activates mTOR signaling and promotes adult beta-cell replication in mouse primary islets, which can be reversed by the treatment with a well-known mTOR inhibitor, rapamycin. These data suggest that miR-7 acts as a brake on adult beta-cell proliferation. Most importantly, this miR-7-mTOR proliferation axis is conserved in primary human beta-cells, implicating miR-7 as a therapeutic target for diabetes. Diabetes. 62:887-895, 2013
引用
收藏
页码:887 / 895
页数:9
相关论文
共 49 条
[1]   mTORC1 Activation Regulates β-Cell Mass and Proliferation by Modulation of Cyclin D2 Synthesis and Stability [J].
Balcazar, Norman ;
Sathyamurthy, Aruna ;
Elghazi, Lynda ;
Gould, Aaron ;
Weiss, Aaron ;
Shiojima, Ichiro ;
Walsh, Kenneth ;
Bernal-Mizrachi, Ernesto .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (12) :7832-7842
[2]   MicroRNA-124a regulates Foxa2 expression and intracellular signaling in pancreatic β-cell lines [J].
Baroukh, Nadine ;
Ravier, Magalie A. ;
Loder, Merewyn K. ;
Hill, Elaine V. ;
Bounacer, Ali ;
Scharfmann, Raphael ;
Rutter, Guy A. ;
Van Obberghen, Emmanuel .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (27) :19575-19588
[3]   Islet β cell expression of constitutively active Akt1/PKBα induces striking hypertrophy, hyperplasia, and hyperinsulinemia [J].
Bernal-Mizrachi, E ;
Wen, W ;
Stahlhut, S ;
Welling, CM ;
Permutt, MA .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 108 (11) :1631-1638
[4]   Quantitative differential expression analysis reveals miR-7 as major islet microRNA [J].
Bravo-Egana, Valia ;
Rosero, Samuel ;
Molano, R. Damaris ;
Pileggi, Antonello ;
Ricordi, Camillo ;
Dominguez-Bendala, Juan ;
Pastori, Ricardo L. .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2008, 366 (04) :922-926
[5]   β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes [J].
Butler, AE ;
Janson, J ;
Bonner-Weir, S ;
Ritzel, R ;
Rizza, RA ;
Butler, PC .
DIABETES, 2003, 52 (01) :102-110
[6]   The replication of β cells in normal physiology, in disease and for therapy [J].
Butler, Peter C. ;
Meier, Juris J. ;
Butler, Alexandra E. ;
Bhushan, Anil .
NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM, 2007, 3 (11) :758-768
[7]   PDGF signalling controls age-dependent proliferation in pancreatic β-cells [J].
Chen, Hainan ;
Gu, Xueying ;
Liu, Yinghua ;
Wang, Jing ;
Wirt, Stacey E. ;
Bottino, Rita ;
Schorle, Hubert ;
Sage, Julien ;
Kim, Seung K. .
NATURE, 2011, 478 (7369) :349-+
[8]   MicroRNA miR-7 is preferentially expressed in endocrine cells of the developing and adult human pancreas [J].
Correa-Medina, Mayrin ;
Bravo-Egana, Valia ;
Rosero, Samuel ;
Ricordi, Camillo ;
Edlund, Helena ;
Diez, Juan ;
Pastori, Ricardo L. .
GENE EXPRESSION PATTERNS, 2009, 9 (04) :193-199
[9]   A SELECTIVE DECREASE IN THE BETA-CELL MASS OF HUMAN ISLETS TRANSPLANTED INTO DIABETIC NUDE-MICE [J].
DAVALLI, AM ;
OGAWA, Y ;
RICORDI, C ;
SCHARP, DW ;
BONNERWEIR, S ;
WEIR, GC .
TRANSPLANTATION, 1995, 59 (06) :817-820
[10]   Regulation of β-cell mass and function by the Akt/protein kinase B signalling pathway [J].
Elghazi, L. ;
Rachdi, L. ;
Weiss, A. J. ;
Cras-Meneur, C. ;
Bernal-Mizrachi, E. .
DIABETES OBESITY & METABOLISM, 2007, 9 :147-157