A Novel Role For Serum Response Factor in Neuronal Survival

Abstract

Recent studies indicate that neuroprotection afforded by brain-derived neurotrophic factor (BDNF) is mediated by extracellular signalregulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3K). However, the mechanisms by which ERK and PI3K exert neuroprotection are not completely understood. Because ERK1/2 and PI3K both stimulate serum response element (SRE)-mediated gene expression, and serum response factor (SRF) is indispensable for SRE-mediated transcription, we investigated whether SRF contributes to ERK1/2 and PI3K neuroprotection. To accomplish this goal, we used an established experimental paradigm in which BDNF protects postnatal cortical neurons against both trophic deprivation and camptothecin-induced DNA damage. BDNF protection against camptothecin is mediated primarily by ERK1/2 activation, whereas its protection against trophic deprivation is mainly through stimulation of the PI3K pathway (Hetman et al., 1999). Here we demonstrate that expression of a wild-type SRF is sufficient to protect postnatal cortical neurons against camptothecin or trophic deprivation. Expression of a dominant-negative SRF partially reversed BDNF neuroprotection against both apoptotic insults. Moreover, the dominant-negative SRF inhibited neuroprotection against trophic withdrawal afforded by expression of a constitutive active PI3K. In addition, protection against camptothecin by expression of constitutive active mitogenactivated protein kinase kinase 1, an upstream kinase that activates ERK1/2, was also blocked by expression of the dominant-negative SRF. These data suggest that SRF is both necessary and sufficient for BDNF neuroprotection of cortical neurons against trophic deprivation and DNA damage. Our data provide a direct demonstration of a biological function of SRF in neurons and a novel downstream neuroprotective mechanism common to both ERK1/2 and PI3K pathways.

Role of Megakaryoblastic Acute Leukemia-1 in ERK1/2-Dependent Stimulation of Serum Response Factor-Driven Transcription by BDNF or Increased Synaptic Activity

“…In addition to ERK1/2, SRF activity may be regulated by PI3K. PI3K contributed to TCF-independent activation of SRF in NGFstimulated PC12 cells and BDNF activation of an SRE reporter in cultured cortical neurons (Poser et al, 2000;Chang et al, 2004). In our hands, PI3K was neither required nor sufficient to activate MKL1/SRF-driven transcription.…”

“…SRF regulation by ERK1/2 is well established (for review, see Shaw and Saxton, 2003) and was demonstrated in cultured primary neurons responding to BDNF (Chang et al, 2004). The major mechanism mediating that effect has been proposed to rely on ERK1/ 2-mediated phosphorylation of the p62TCF/Elk-1 (Shaw and Saxton, 2003).…”

Basic Fibroblast Growth Factor Protects against Rotenone-Induced Dopaminergic Cell Death through Activation of Extracellular Signal-Regulated Kinases 1/2 and Phosphatidylinositol-3 Kinase Pathways

“…bFGF induced phosphorylation and activation of ERK1/2 and PI3-kinase signaling pathways. Both ERK1/2 and PI3-kinase signaling pathways have been implicated in protecting various types of neurons against different injuries (Xia et al, 1995;Dudek et al, 1997;Hetman et al, 1999;Hetman and Xia, 2000;Chang et al, 2004). However, their involvement in neuroprotection in Parkinson's disease models is essentially uncharacterized, although recent reports implicated them in GDNF or NGF protection against 6-OHDA ( Salinas et al, 2003;Ugarte et al, 2003).…”

“…Both ERK1/2 and PI3-kinase pathways are crucial for bFGF protection against rotenone bFGF can activate several signal transduction pathways that have been implicated in neuroprotection against different forms of cellular insult (Hetman et al, 1999;Desire et al, 2000;Pardo et al, 2002;Chang et al, 2004). To investigate the underlying mechanisms responsible for bFGF protection against rotenone, SH-SY5Y cells were stimulated with bFGF for 0 -30 min and analyzed for activation of ERK1/2 and PI3-kinase pathways by Western blot analysis.…”

Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways

“…Accordingly, the Ras/MAPK and the PI3-K pathways are known to stimulate the serum response factor (SRF), which plays a role in neuronal survival. 77 Neurotrophins activate other transcription factors, which can also upregulate the expression of several target genes. Akt was also shown to inhhibit Forkhead transcription factors, inhibiting their ability to induce the expression of death genes.…”