Inhibition of ATF-3 expression by B-Raf mediates the neuroprotective action of GW5074

Journal of Neurochemistry
Hsin-Mei ChenSantosh R D'Mello

Abstract

GW5074 a brain-permeable 3' substituted indolone, protects neurons from death in culture and in an in vivo paradigm of neurodegeneration. Using low potassium (LK) induced apoptosis of cerebellar granule neurons, we report here that the protective action of GW5074 is mediated through the activation of B-Raf. Over-expression of a kinase-dead form of B-Raf blocks the ability of GW5074 to neuroprotect, whereas over-expression of active forms of B-Raf protect even in the absence of GW5074. Although mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated protein kinase (ERK) are activated by GW5074, pharmacological inhibition of MEK-ERK signaling by U0126 or PD98059 does not reduce neuroprotection suggesting that B-Raf signals through a non-canonical signaling pathway. GeneChip microarray analyses identified activating transcription factor-3 (ATF-3) as a gene whose expression is induced by LK but that is negatively regulated by GW5074. Forced inhibition of ATF-3 expression using siRNA protects neurons against LK-induced apoptosis, whereas the over-expression of ATF-3 blocks GW5074-mediated neuroprotection. Not unexpectedly, expression of active B-Raf inhibits the apoptosis-associated increase in ATF-3 express...Continue Reading

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Citations

Mar 3, 2012·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Amteshwar Singh Jaggi, Nirmal Singh
Sep 14, 2011·Neuro-Signals·Diana NascimentoFani Lourença Neto
Jun 16, 2009·Molecular Carcinogenesis·Jelena UrosevicMariano Barbacid
Oct 12, 2010·Journal of Neuroscience Research·Huai-Lu Chen, Santosh R D'Mello
Sep 18, 2008·The Journal of General Virology·Minetaro AritaHiroyuki Shimizu
Feb 14, 2012·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Amteshwar Singh Jaggi, Nirmal Singh
Dec 31, 2020·Biomolecules·Vanessa Loaiza-CanoDamião Pergentino de Sousa

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis