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

Elucidating the mechanism underlying the poor proliferative capacity of adult pancreatic β-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 β-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 β-cell proliferation. Most importantly, this miR-7–mTOR proliferation axis is conserved in primary human β-cells, implicating miR-7 as a therapeutic target for diabetes.

[1]  D. Stoffers,et al.  On the origin of the beta cell. , 2008, Genes & development.

[2]  C. Ricordi,et al.  Antisense miR-7 Impairs Insulin Expression in Developing Pancreas and in Cultured Pancreatic Buds , 2012, Cell transplantation.

[3]  J. Friedman,et al.  MicroRNA Profiling Identifies miR-29 as a Regulator of Disease-associated Pathways in Experimental Biliary Atresia , 2012, Journal of pediatric gastroenterology and nutrition.

[4]  S. Nagata,et al.  Mnk2 and Mnk1 Are Essential for Constitutive and Inducible Phosphorylation of Eukaryotic Initiation Factor 4E but Not for Cell Growth or Development , 2004, Molecular and Cellular Biology.

[5]  Anil Bhushan,et al.  The replication of beta cells in normal physiology, in disease and for therapy. , 2007, Nature clinical practice. Endocrinology & metabolism.

[6]  David Haussler,et al.  The UCSC genome browser database: update 2007 , 2006, Nucleic Acids Res..

[7]  K. Takane,et al.  Gene transfer of constitutively active Akt markedly improves human islet transplant outcomes in diabetic severe combined immunodeficient mice. , 2005, Diabetes.

[8]  R. Scharfmann,et al.  l-Leucine Alters Pancreatic β-Cell Differentiation and Function via the mTor Signaling Pathway , 2012, Diabetes.

[9]  M. Permutt,et al.  Islet β cell expression of constitutively active Akt1/PKBα induces striking hypertrophy, hyperplasia, and hyperinsulinemia , 2001 .

[10]  John S Mattick,et al.  Regulation of Epidermal Growth Factor Receptor Signaling in Human Cancer Cells by MicroRNA-7* , 2009, Journal of Biological Chemistry.

[11]  J. Qin,et al.  SIN1/MIP1 Maintains rictor-mTOR Complex Integrity and Regulates Akt Phosphorylation and Substrate Specificity , 2006, Cell.

[12]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[13]  J. Kushner,et al.  Very Slow Turnover of β-Cells in Aged Adult Mice , 2005 .

[14]  W. Uhl,et al.  Partial Pancreatectomy in Adult Humans Does Not Provoke β-Cell Regeneration , 2008, Diabetes.

[15]  S. Bonner-Weir,et al.  A selective decrease in the beta cell mass of human islets transplanted into diabetic nude mice. , 1995, Transplantation.

[16]  M. Behlke,et al.  Pancreas-enriched miRNA refines endocrine cell differentiation , 2012, Development.

[17]  N. Baroukh,et al.  MicroRNA-124a Regulates Foxa2 Expression and Intracellular Signaling in Pancreatic β-Cell Lines* , 2007, Journal of Biological Chemistry.

[18]  P. Haentjens,et al.  β-Cell Replication Is Increased in Donor Organs From Young Patients After Prolonged Life Support , 2010, Diabetes.

[19]  M. Gambello,et al.  Disruption of Tsc2 in pancreatic β cells induces β cell mass expansion and improved glucose tolerance in a TORC1-dependent manner , 2008, Proceedings of the National Academy of Sciences.

[20]  A. F. Stewart,et al.  Survey of the Human Pancreatic β-Cell G1/S Proteome Reveals a Potential Therapeutic Role for Cdk-6 and Cyclin D1 in Enhancing Human β-Cell Replication and Function In Vivo , 2009, Diabetes.

[21]  E. Izaurralde,et al.  Gene silencing by microRNAs: contributions of translational repression and mRNA decay , 2011, Nature Reviews Genetics.

[22]  D. Harlan,et al.  Significant human beta-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating. , 2010, The Journal of clinical endocrinology and metabolism.

[23]  R. Burcelin,et al.  Hypoinsulinaemia, glucose intolerance and diminished β-cell size in S6K1-deficient mice , 2000, Nature.

[24]  Rika Nakayama,et al.  Upregulation of the Mammalian Target of Rapamycin Complex 1 Pathway by Ras Homolog Enriched in Brain in Pancreatic β-Cells Leads to Increased β-Cell Mass and Prevention of Hyperglycemia , 2009, Diabetes.

[25]  P. Sharp,et al.  MicroRNA functions in stress responses. , 2010, Molecular cell.

[26]  Robert A. Rizza,et al.  β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes , 2003, Diabetes.

[27]  J. Sage,et al.  PDGF signalling controls age-dependent proliferation in pancreatic β-cells , 2011, Nature.

[28]  L. Rachdi,et al.  Regulation of β‐cell mass and function by the Akt/protein kinase B signalling pathway , 2007, Diabetes, obesity & metabolism.

[29]  G. Rutter,et al.  miR-29a and miR-29b Contribute to Pancreatic β-Cell-Specific Silencing of Monocarboxylate Transporter 1 (Mct1) , 2011, Molecular and Cellular Biology.

[30]  K. Inoki,et al.  TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling , 2002, Nature Cell Biology.

[31]  W. Uhl,et al.  Partial pancreatectomy in adult humans does not provoke beta-cell regeneration. , 2008, Diabetes.

[32]  J. Kushner,et al.  Very slow turnover of beta-cells in aged adult mice. , 2005, Diabetes.

[33]  I. Shiojima,et al.  mTORC1 Activation Regulates β-Cell Mass and Proliferation by Modulation of Cyclin D2 Synthesis and Stability* , 2009, Journal of Biological Chemistry.

[34]  M. Birnbaum,et al.  Three-amino-acid-loop-extension homeodomain factor Meis3 regulates cell survival via PDK1 , 2010, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Mcdaniel,et al.  Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins, and growth factors in islets. , 2004, Diabetes.

[36]  M. Permutt,et al.  Islet beta cell expression of constitutively active Akt1/PKB alpha induces striking hypertrophy, hyperplasia, and hyperinsulinemia. , 2001, The Journal of clinical investigation.

[37]  Michael T. McManus,et al.  MicroRNA Expression Is Required for Pancreatic Islet Cell Genesis in the Mouse , 2007, Diabetes.

[38]  C. Ricordi,et al.  MicroRNA miR-7 is preferentially expressed in endocrine cells of the developing and adult human pancreas. , 2009, Gene expression patterns : GEP.

[39]  Y. Dor,et al.  miRNAs control insulin content in pancreatic β‐cells via downregulation of transcriptional repressors , 2011, The EMBO journal.

[40]  A. Kolokythas,et al.  MicroRNA-7 targets IGF1R (insulin-like growth factor 1 receptor) in tongue squamous cell carcinoma cells. , 2010, The Biochemical journal.

[41]  Dudley Lamming,et al.  Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity , 2012, Science.

[42]  Ming Yi,et al.  miRNA-7 attenuation in Schwannoma tumors stimulates growth by upregulating three oncogenic signaling pathways. , 2011, Cancer research.

[43]  M. Büchler,et al.  Impaired islet turnover in human donor pancreata with aging. , 2008, European journal of endocrinology.

[44]  Ling Tian,et al.  MicroRNA‐7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3‐kinase/Akt pathway in hepatocellular carcinoma , 2012, Hepatology.

[45]  Selene L. Fernandez-Valverde,et al.  MicroRNAs in β-Cell Biology, Insulin Resistance, Diabetes and Its Complications , 2011, Diabetes.

[46]  N. Rajewsky,et al.  A pancreatic islet-specific microRNA regulates insulin secretion , 2004, Nature.

[47]  D. Sabatini,et al.  mTOR: from growth signal integration to cancer, diabetes and ageing , 2010, Nature Reviews Molecular Cell Biology.

[48]  C. Ricordi,et al.  Quantitative differential expression analysis reveals miR-7 as major islet microRNA. , 2008, Biochemical and biophysical research communications.

[49]  P. Halban,et al.  Proliferation of sorted human and rat beta cells , 2007, Diabetologia.

[50]  Yunqing Li,et al.  microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. , 2008, Cancer research.

[51]  J. Rinn,et al.  Non-coding RNAs as regulators of embryogenesis , 2011, Nature Reviews Genetics.

[52]  S. Pyronnet,et al.  Phosphorylation of the cap-binding protein eIF4E by the MAPK-activated protein kinase Mnk1. , 2000, Biochemical pharmacology.

[53]  Mary Goldman,et al.  The UCSC Genome Browser database: update 2011 , 2010, Nucleic Acids Res..