ETS-domain transcription factor Elk-1 mediates neuronal survival: SMN as a potential target

Abstract

Elk-1 belongs to the ternary complex factors (TCFs) subfamily of the ETS domain proteins, and plays a critical role in the expression of immediate-early genes (IEGs) upon mitogen stimulation and activation of the mitogen-activated protein kinase (MAPK) cascade. The association of TCFs with serum response elements (SREs) on IEG promoters has been widely studied and a role for Elk-1 in promoting cell cycle entry has been determined. However, the presence of the ETS domain transcription factor Elk-1 in axons and dendrites of post-mitotic adult brain neurons has implications for an alternative function for Elk-1 in neurons other than controlling proliferation. In this study, possible alternative roles for Elk-1 in neurons were investigated, and it was demonstrated that blocking TCF-mediated transactivation in neuronal cells leads to apoptosis through a caspase-dependent mechanism. Indeed RNAi-mediated depletion of endogenous Elk-1 results in increased caspase activity. Conversely, overexpression of either Elk-1 or Elk-VP16 fusion proteins was shown to rescue PC12 cells from chemically-induced apoptosis, and that higher levels of endogenous Elk-1 correlated with longer survival of DRGs in culture. It was shown that Elk-1 regulated the Mcl-1 gene expression required for survival, and that RNAi-mediated degradation of endogenous Elk-1 resulted in elimination of the mcl-1 message. We have further identified the survival-of-motor neuron-1 (SMN1) gene as a novel target of Elk-1, and show that the ets motifs in the SMN1 promoter are involved in this regulation.

Shift from Extracellular Signal-Regulated Kinase to AKT/cAMP Response Element-Binding Protein Pathway Increases Survival-Motor-Neuron Expression in Spinal-Muscular-Atrophy-Like Mice and Patient Cells

“…The lifespan of 0.9% NaCl and 1% DMSO-treated mice (1.66 Ϯ 0.55 d) proved to be similar to 0.9% NaCl-treated mice (1.65 Ϯ 0.62 d; Biondi et al, 2010). Body weight and lifespan recordings were performed every day until the death of the animal.…”

“…Stimulation of the NMDA receptors was achieved by exposing cells to 100 M NMDA, as described previously (Biondi et al, 2010). To evaluate the CREB dependency, carbamoyl]-2-naphthyl dihydrogen phosphate) (10 M; Sigma) was added to the culture.…”

“…A number of groups have identified SMN2 gene-inducing molecules (Chang et al, 2001;Avila et al, 2007;Thurmond et al, 2008;Tsai et al, 2008;Butchbach et al, 2010;Lorson et al, 2010), but so far, most of these agents yielded inconclusive results in clinical trials (Mercuri et al, 2007;Swoboda et al, 2009Swoboda et al, , 2010). An alternative promising therapeutic development for SMA, although as yet unexplored, could be based on the pharmacological correction of molecular mechanisms that are altered in the SMA neuromuscular system, such as the AKT/CREB and ERK signaling pathways (Biondi et al, 2010). In striking contrast to AKT, the kinase ERK was found to be constitutively overactivated in mouse SMA spinal cord (Biondi et al, 2010).…”

“…An alternative promising therapeutic development for SMA, although as yet unexplored, could be based on the pharmacological correction of molecular mechanisms that are altered in the SMA neuromuscular system, such as the AKT/CREB and ERK signaling pathways (Biondi et al, 2010). In striking contrast to AKT, the kinase ERK was found to be constitutively overactivated in mouse SMA spinal cord (Biondi et al, 2010). These observations raise important questions about the potential role of the ERK pathway in the regulation of SMN2 gene expression that can be investigated in type 1 SMA-like mice spinal cord.…”

NF-κB deficit in spinal motoneurons in patients with sporadic amyotrophic lateral sclerosis – a pilot study

“…clearly lowered SMN level; the latter was obviously related to the poor condition of the cells [37]. The continuing SMN expression at the absence of NF-κB in the nucleus suggests that the expression under these conditions is controlled by different transcription factor(s); it has been shown that SMN is a target gene also for Elk-1 [9] and CREB [24]. However, the functionality of the SMN protein complex-dependent motoneuron survival pathway is in serious doubt.…”