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Apoptosis

, 16:1128 | Cite as

Rapamycin protects against dominant negative-HNF1A-induced apoptosis in INS-1 cells

  • Angela M. Farrelly
  • Seán M. Kilbride
  • Caroline Bonner
  • Jochen H. M. Prehn
  • Maria M. Byrne
Original Paper

Abstract

HNF1A-maturity onset diabetes of the young (HNF1A-MODY) is caused by mutations in Hnf1a gene encoding the transcription factor hepatocyte nuclear factor 1alpha (HNF1A). An increased rate of apoptosis has been associated with the decrease in beta-cell mass that is a hallmark of HNF1A-MODY and other forms of diabetes. In a cellular model of HNF1A-MODY, we have recently shown that signalling through mammalian target of rapamycin (mTOR) is decreased by the overexpression of a dominant-negative mutant of HNF1A (DN-HNF1A). mTOR is a protein kinase which has important roles in cell metabolism and growth, but also in cell survival, where it has been shown to be both protective and detrimental. Here, we show that pharmacological inhibition of mTOR activity with rapamycin protected INS-1 cells against DN-HNF1A-induced apoptosis. Rapamycin also prevented DN-HNF1A-induced activation of AMP-activated protein kinase (AMPK), an intracellular energy sensor which we have previously shown to mediate DN-HNF1A-induced apoptosis. Conversely, activation of mTOR with leucine potentiated DN-HNF1A-induced apoptosis. Gene silencing of raptor (regulatory associated protein of mTOR), a subunit of mTOR complex 1 (mTORC1), also conferred protection on INS-1 cells against DN-HNF1A-induced apoptosis, confirming that mTORC1 mediates the protective effect. The potential relevance of this effect with regards to the clinical use of rapamycin as an immunosuppressant in diabetics post-transplantation is discussed.

Keywords

Mammalian target of rapamycin (mTOR) HNF1A-MODY Rapamycin Apoptosis 

Notes

Acknowledgments

This work was funded by Health Research Board (RP/2008/14) and Science Foundation Ireland (08/IN1/1949) grants to J.H.M.P., and from the Health Research Board (RP/2007/316) to M.M.B.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Angela M. Farrelly
    • 1
    • 2
  • Seán M. Kilbride
    • 2
  • Caroline Bonner
    • 2
  • Jochen H. M. Prehn
    • 2
  • Maria M. Byrne
    • 1
  1. 1.Department of EndocrinologyMater Misericordiae University HospitalDublin 7Ireland
  2. 2.Department of Physiology and Medical PhysicsRoyal College of Surgeons in IrelandDublin 2Ireland

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