Insulin-like growth factor-I suppresses degradation of the pro-survival transcription factor myocyte enhancer factor 2D (MEF2D) during neuronal apoptosis

• Published in: Hormone and metabolic research Vol. 35; no. 11-12; p. 763
• Main Authors: Butts, B D, Linseman, D A, Le, S S, Laessig, T A, Heidenreich, K A
• Format: Journal Article
• Language: English
• Published: Germany 01.11.2003
• Subjects: Animals; Animals, Newborn; Apoptosis - drug effects; Cell Survival - drug effects; Cells, Cultured; Cerebellum - cytology; Cerebellum - drug effects; Cerebellum - physiology; Cytarabine - pharmacology; DNA-Binding Proteins - metabolism; Genes, Reporter; Insulin-Like Growth Factor I - pharmacology; MEF2 Transcription Factors; Myogenic Regulatory Factors; Neurons - cytology; Neurons - drug effects; Neurons - physiology; Phosphorylation; Potassium - pharmacology; Protein Processing, Post-Translational - drug effects; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Transcription Factors - metabolism; Transfection
• ISSN: 0018-5043
• DOI: 10.1055/s-2004-814148

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.