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

Hormone and Metabolic Research, Inhaltsverzeichnis

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

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

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References

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