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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.
J Neurosci Res. 2005 Jul 15; 81(2):226-34.JN

Abstract

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.

Authors+Show Affiliations

Department of Medicine, Rhode Island Hospital and Brown Medical School, Providence, Rhode Island, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15931671

Citation

Wiedmann, M, et al. "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." Journal of Neuroscience Research, vol. 81, no. 2, 2005, pp. 226-34.
Wiedmann M, Wang X, Tang X, et al. 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. J Neurosci Res. 2005;81(2):226-34.
Wiedmann, M., Wang, X., Tang, X., Han, M., Li, M., & Mao, Z. (2005). 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. Journal of Neuroscience Research, 81(2), 226-34.
Wiedmann M, et al. 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. J Neurosci Res. 2005 Jul 15;81(2):226-34. PubMed PMID: 15931671.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Wiedmann,M, AU - Wang,X, AU - Tang,X, AU - Han,M, AU - Li,M, AU - Mao,Z, PY - 2005/6/3/pubmed PY - 2005/11/4/medline PY - 2005/6/3/entrez SP - 226 EP - 34 JF - Journal of neuroscience research JO - J Neurosci Res VL - 81 IS - 2 N2 - 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. SN - 0360-4012 UR - https://www.unboundmedicine.com/medline/citation/15931671/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_ L2 - https://doi.org/10.1002/jnr.20556 DB - PRIME DP - Unbound Medicine ER -