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Suppression of a MEF2-KLF6 survival pathway by PKA signaling promotes apoptosis in embryonic hippocampal neurons.
J Neurosci. 2012 Feb 22; 32(8):2790-803.JN

Abstract

In the mammalian nervous system, regulation of transcription factor activity is a crucial determinant of neuronal cell survival, differentiation, and death. The myocyte enhancer factor 2 (MEF2) transcription factors have been implicated in cellular processes underlying neuronal survival and differentiation. A core component of the MEF2 complex is the MEF2D subunit. Recently, we reported that cAMP-dependent protein kinase (cAMP/PKA) signaling negatively regulates MEF2D function in myogenic cells. Here, we assessed whether cAMP signaling converges on the prosurvival role of MEF2D in Sprague Dawley rat embryonic (E18) hippocampal neurons. Initially, we observed that experimental induction of cAMP/PKA signaling promotes apoptosis in primary hippocampal neurons as indicated by TUNEL and FACS analysis. Luciferase reporter gene assays revealed that PKA potently represses MEF2D trans-activation properties in neurons. This effect was largely reversed by engineered neutralizing mutations of PKA phospho-acceptor sites on MEF2D (S121/190A). Krüppel-like factor 6 (KLF6) was identified as a key transcriptional target of MEF2 in hippocampal neurons, and siRNA-mediated knockdown of KLF6 expression promotes neuronal cell death and also antagonizes the prosurvival role of MEF2D. These observations have important implications for understanding the pathways controlling cell survival and death in the mammalian nervous system.

Authors+Show Affiliations

Department of Biology, York University, Toronto, Ontario, Canada.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22357862

Citation

Salma, Jahan, and John C. McDermott. "Suppression of a MEF2-KLF6 Survival Pathway By PKA Signaling Promotes Apoptosis in Embryonic Hippocampal Neurons." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 32, no. 8, 2012, pp. 2790-803.
Salma J, McDermott JC. Suppression of a MEF2-KLF6 survival pathway by PKA signaling promotes apoptosis in embryonic hippocampal neurons. J Neurosci. 2012;32(8):2790-803.
Salma, J., & McDermott, J. C. (2012). Suppression of a MEF2-KLF6 survival pathway by PKA signaling promotes apoptosis in embryonic hippocampal neurons. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 32(8), 2790-803. https://doi.org/10.1523/JNEUROSCI.3609-11.2012
Salma J, McDermott JC. Suppression of a MEF2-KLF6 Survival Pathway By PKA Signaling Promotes Apoptosis in Embryonic Hippocampal Neurons. J Neurosci. 2012 Feb 22;32(8):2790-803. PubMed PMID: 22357862.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Suppression of a MEF2-KLF6 survival pathway by PKA signaling promotes apoptosis in embryonic hippocampal neurons. AU - Salma,Jahan, AU - McDermott,John C, PY - 2012/2/24/entrez PY - 2012/2/24/pubmed PY - 2012/4/17/medline SP - 2790 EP - 803 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 32 IS - 8 N2 - In the mammalian nervous system, regulation of transcription factor activity is a crucial determinant of neuronal cell survival, differentiation, and death. The myocyte enhancer factor 2 (MEF2) transcription factors have been implicated in cellular processes underlying neuronal survival and differentiation. A core component of the MEF2 complex is the MEF2D subunit. Recently, we reported that cAMP-dependent protein kinase (cAMP/PKA) signaling negatively regulates MEF2D function in myogenic cells. Here, we assessed whether cAMP signaling converges on the prosurvival role of MEF2D in Sprague Dawley rat embryonic (E18) hippocampal neurons. Initially, we observed that experimental induction of cAMP/PKA signaling promotes apoptosis in primary hippocampal neurons as indicated by TUNEL and FACS analysis. Luciferase reporter gene assays revealed that PKA potently represses MEF2D trans-activation properties in neurons. This effect was largely reversed by engineered neutralizing mutations of PKA phospho-acceptor sites on MEF2D (S121/190A). Krüppel-like factor 6 (KLF6) was identified as a key transcriptional target of MEF2 in hippocampal neurons, and siRNA-mediated knockdown of KLF6 expression promotes neuronal cell death and also antagonizes the prosurvival role of MEF2D. These observations have important implications for understanding the pathways controlling cell survival and death in the mammalian nervous system. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/22357862/Suppression_of_a_MEF2_KLF6_survival_pathway_by_PKA_signaling_promotes_apoptosis_in_embryonic_hippocampal_neurons_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=22357862 DB - PRIME DP - Unbound Medicine ER -