TY - JOUR
T1 - The canonical nuclear factor-κB pathway regulates cell survival in a developmental model of spinal cord motoneurons
AU - Tasheva, Stefka
AU - Garcera, Ana
AU - Gou-Fabregas, Myriam
AU - Encinas, Mario
AU - Dolcet, Xavier
AU - Soler, Rosa M.
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/4/27
Y1 - 2011/4/27
N2 - In vivo and in vitro motoneuron survival depends on the support of neurotrophic factors. These factors activate signaling pathways related to cell survival or inactivate proteins involved in neuronal death. In the present work, we analyzed the involvement of the nuclear factor-KB (NF-kB) pathway in mediating mouse spinal cord motoneuron survival promoted by neurotrophic factors. This pathway comprises ubiquitously expressed transcription factors that could be activated by two different routes: the canonical pathway, associated with IKKa/IKK/3 kinase phosphorylation and nuclear translocation RelA (p65)/p50 transcription factors; and the noncanonical pathway, related to IKKa kinase homodimer phosphorylation and RelB/p52 transcription factor activation. In our system, we show that neurotrophic factors treatment induced IKKa and IKK/3 phosphorylation and RelA nuclear translocation, suggesting NF-kB pathway activation. Protein levels of different members of the canonical or noncanonical pathways were reduced in a primary culture of isolated embryonic motoneurons using an interference RNA approach. Even in the presence of neurotrophic factors, selective reduction of IKKa, IKK/3, or RelA proteins induced cell death. In contrast, RelB protein reduction did not have a negative effect on motoneuron survival. Together these results demonstrated that the canonical NF-kB pathway mediates motoneuron survival induced by neurotrophic factors, and the noncanonical pathway is not related to this survival effect. Canonical NF-kB blockade induced an increase of Bim protein level and apoptotic cell death. Bcl-xL overexpression or Bax reduction counteracted this apoptotic effect. Finally, RelA knockdown causes changes of CREB and Smn protein levels.
AB - In vivo and in vitro motoneuron survival depends on the support of neurotrophic factors. These factors activate signaling pathways related to cell survival or inactivate proteins involved in neuronal death. In the present work, we analyzed the involvement of the nuclear factor-KB (NF-kB) pathway in mediating mouse spinal cord motoneuron survival promoted by neurotrophic factors. This pathway comprises ubiquitously expressed transcription factors that could be activated by two different routes: the canonical pathway, associated with IKKa/IKK/3 kinase phosphorylation and nuclear translocation RelA (p65)/p50 transcription factors; and the noncanonical pathway, related to IKKa kinase homodimer phosphorylation and RelB/p52 transcription factor activation. In our system, we show that neurotrophic factors treatment induced IKKa and IKK/3 phosphorylation and RelA nuclear translocation, suggesting NF-kB pathway activation. Protein levels of different members of the canonical or noncanonical pathways were reduced in a primary culture of isolated embryonic motoneurons using an interference RNA approach. Even in the presence of neurotrophic factors, selective reduction of IKKa, IKK/3, or RelA proteins induced cell death. In contrast, RelB protein reduction did not have a negative effect on motoneuron survival. Together these results demonstrated that the canonical NF-kB pathway mediates motoneuron survival induced by neurotrophic factors, and the noncanonical pathway is not related to this survival effect. Canonical NF-kB blockade induced an increase of Bim protein level and apoptotic cell death. Bcl-xL overexpression or Bax reduction counteracted this apoptotic effect. Finally, RelA knockdown causes changes of CREB and Smn protein levels.
UR - http://www.scopus.com/inward/record.url?scp=79955784663&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0206-11.2011
DO - 10.1523/JNEUROSCI.0206-11.2011
M3 - Article
C2 - 21525290
AN - SCOPUS:79955784663
SN - 0270-6474
VL - 31
SP - 6493
EP - 6503
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 17
ER -