mTORC1 activation regulates β-cell mass and proliferation by modulation of cyclin D2 synthesis and stability

Norman Balcazar, Aruna Sathyamurthy, Lynda Elghazi, Aaron Gould, Aaron Weiss, Ichiro Shiojima, Kenneth Walsh, Ernesto Bernal-Mizrachi

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81 Scopus citations

Abstract

Growth factors, insulin signaling, and nutrients are important regulators of β-cell mass and function. The events linking these signals to the regulation of β-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 β-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 β-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 β-cells to insulin resistance.

Original languageEnglish (US)
Pages (from-to)7832-7842
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number12
DOIs
StatePublished - Mar 20 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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