Insulin-like Growth Factor-I Suppresses Degradation of the Pro-survival Transcription Factor Myocyte Enhancer Factor 2D (MEF2D) During Neuronal Apoptosis

B. D. Butts; D. A. Linseman; S. S. Le; T. A. Laessig; K. A. Heidenreich

doi:10.1055/s-2004-814148

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Horm Metab Res 2003; 35(11/12): 763-770
DOI: 10.1055/s-2004-814148

Original

Insulin-like Growth Factor-I Suppresses Degradation of the Pro-survival Transcription Factor Myocyte Enhancer Factor 2D (MEF2D) During Neuronal Apoptosis

B. D. Butts¹ , D. A. Linseman¹ , S. S. Le¹ , T. A. Laessig¹ , K. A. Heidenreich¹

¹Department of Pharmacology, University of Colorado Health Sciences Center, and the Denver Veterans Affairs Medical Center, Denver, CO 80262, USA

Further Information

Publication History

Received 30 August 2003

Accepted after Revision 22 October 2003

Publication Date:
07 January 2004 (online)

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Abstract

Cultured rat cerebellar granule neurons (CGNs) require depolarization-mediated calcium influx for survival. Calcium regulates the activity of the pro-survival transcription factor, myocyte enhancer factor 2D (MEF2D). MEF2D is hyperphosphorylated and degraded in CGNs undergoing apoptosis induced by lowering the extracellular potassium concentration from 25 mM to 5 mM. Since insulin-like growth factor-I (IGF-I) is known to protect CGNs from apoptotic cell death, we investigated the effects of IGF-I on MEF2D processing during apoptosis. IGF-I administered during the apoptotic insult did not prevent the hyperphosphorylation of MEF2D and consequential loss of DNA binding. However, IGF-I significantly blocked the degradation of MEF2D. Furthermore, IGF-I had no effect on the initial loss of MEF2 transcriptional activity following hyperphosphorylation, but the recovery of MEF2 activity following restoration of intracellular calcium was significantly increased by IGF-I. We conclude that IGF-I blocks the degradation of MEF2D and enhances recovery of MEF2 activity by protecting MEF2D from caspase-dependent cleavage during apoptosis. These results suggest that IGF-I can prolong the time of commitment to irreversible cell death and enhance the recovery of neurons subjected to an acute apoptotic stimulus by preserving the activity of the pro-survival factor MEF2D.

Key words

Cerebellar granule neurons - Neurodegeneration - Programmed cell death - Caspases - Signal transduction

References

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