Document Detail


mTORC1 activation regulates beta-cell mass and proliferation by modulation of cyclin D2 synthesis and stability.
MedLine Citation:
PMID:  19144649     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Norman Balcazar; Aruna Sathyamurthy; Lynda Elghazi; Aaron Gould; Aaron Weiss; Ichiro Shiojima; Kenneth Walsh; Ernesto Bernal-Mizrachi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-01-14
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 Mar 
Date Detail:
Created Date:  2009-03-16     Completed Date:  2009-05-14     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7832-42     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Cycle
Cell Line
Cell Size
Cyclin D2
Cyclin D3
Cyclin-Dependent Kinase 4 / genetics,  metabolism
Cyclins / biosynthesis*,  genetics,  metabolism
Immunosuppressive Agents / adverse effects,  pharmacology
Insulin Resistance / genetics
Insulin-Secreting Cells / cytology,  metabolism*
Islets of Langerhans Transplantation
Mice
Mice, Transgenic
Multiprotein Complexes
Protein Biosynthesis / drug effects,  physiology*
Protein Stability / drug effects
Proteins
Signal Transduction / drug effects,  physiology*
Sirolimus / adverse effects,  pharmacology
TOR Serine-Threonine Kinases
Transcription Factors / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
R01 DK073716/DK/NIDDK NIH HHS; R01 DK073716-02/DK/NIDDK NIH HHS; R01 DK073716-03/DK/NIDDK NIH HHS; R01DK073716-01/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Ccnd2 protein, mouse; 0/Ccnd3 protein, mouse; 0/Cyclin D2; 0/Cyclin D3; 0/Cyclins; 0/Immunosuppressive Agents; 0/Multiprotein Complexes; 0/Proteins; 0/Transcription Factors; 0/mechanistic target of rapamycin complex 1; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.22/Cdk4 protein, mouse; EC 2.7.11.22/Cyclin-Dependent Kinase 4; W36ZG6FT64/Sirolimus
Comments/Corrections

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