title: mTORC1 activation regulates beta-cell mass and proliferation by modulation of cyclin D2 synthesis and stability.
abstract: Growth factors, insulin signaling, and nutrients are important regulators of beta-cell mass and function. The events linking these signals to the regulation of beta-cell mass are not completely understood. The mTOR pathway integrates signals from growth factors and nutrients. Here, we evaluated the role of the mTOR/raptor (mTORC1) signaling in proliferative conditions induced by controlled activation of Akt signaling. These experiments show that the mTORC1 is a major regulator of beta-cell cycle progression by modulation of cyclin D2, D3, and Cdk4 activity. The regulation of cell cycle progression by mTORC1 signaling resulted from modulation of the synthesis and stability of cyclin D2, a critical regulator of beta-cell cycle, proliferation, and mass. These studies provide novel insights into the regulation of cell cycle by the mTORC1, provide a mechanism for the antiproliferative effects of rapamycin, and imply that the use of rapamycin could negatively impact the success of islet transplantation and the adaptation of beta-cells to insulin resistance.
authors.affiliation: Washington University School of Medicine, Division of Endocrinology, Metabolism & Lipid Research, St. Louis, Missouri, 63110, USA.
authors.forename: Norman
authors.initials: N
authors.lastname: Balcazar
authors.forename: Aruna
authors.initials: A
authors.lastname: Sathyamurthy
authors.forename: Lynda
authors.initials: L
authors.lastname: Elghazi
authors.forename: Aaron
authors.initials: A
authors.lastname: Gould
authors.forename: Aaron
authors.initials: A
authors.lastname: Weiss
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D048429:Cell Size; D056742:Cyclin D2; D056743:Cyclin D3; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D055550:Protein Stability / Q000187:drug effects; D011506:Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000009:adverse effects / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D020123:Sirolimus