PI3K/Akt-dependent regulation of the transcription factor myocyte enhancer factor-2 in insulin-like growth factor-1- and membrane depolarization-mediated survival of cerebellar granule neurons.
Survival signals such as insulin-like growth factor-1 (IGF-1) or membrane depolarization convey their neuronal protective effects through the activation of signaling networks and nuclear factors. In cerebellar granule neurons, IGF-1 mediates survival primarily through the PI3K/Akt pathway. The function of the transcription factor myocyte enhancer factor-2 (MEF2) is required for mediating membrane depolarization-dependent neuronal survival. However, whether PI3K/Akt regulates MEF2 and the role of MEF2 in IGF-1-mediated survival of neurons are unknown. In addition, the contribution of the PI3K/Akt pathway in membrane depolarization-induced neuronal survival remains undefined. We show here that the PI3K/Akt pathway promotes the survival of cerebellar granule neurons derived from Long-Evans rats following IGF-1 stimulation or membrane depolarization through regulation of MEF2 activity. IGF-1 stimulated the gene transactivation activity of MEF2 and its DNA binding potential. Moreover, regulation of MEF2 function by IGF-1 was dependent on the activity of the PI3K/Akt signaling pathway. Blocking MEF2 function reduced IGF-1-induced survival of cerebellar granule neurons. Membrane depolarization stimulated phosphorylation of Akt in cerebellar granule neurons. Blocking of the PI3K/Akt pathway with either a pharmacological inhibitor of PI3K, LY294002, or dominant negative mutants of PI3K and Akt inhibited the membrane depolarization-induced increase in MEF2 transactivation as well as its DNA binding activity and reduced neuronal survival. Together, these findings provide clear evidence to support an important role of the PI3K/Akt pathway in the regulation of nuclear survival factor MEF2 upon either IGF-1 stimulation or membrane depolarization, thus placing MEF2 as a novel downstream effector of the PI3K/Akt pathway in neurons.
Wiedmann
M
M
Department of Medicine, Rhode Island Hospital and Brown Medical School, Providence, Rhode Island, USA.
Wang
X
X
Tang
X
X
Han
M
M
Li
M
M
Mao
Z
Z
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000201:enzymology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D020318:Rats, Long-Evans; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D007334:Insulin-Like Growth Factor I; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; C494920:Akt1 protein, rat