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


Demir O., Aysit N., Onder Z., Turkel N., Ozturk G., Sharrocks A. D. , ...Daha Fazla

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, cilt.1812, ss.652-662, 2011 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 1812 Konu: 6
  • Basım Tarihi: 2011
  • Doi Numarası: 10.1016/j.bbadis.2011.02.012
  • Dergi Adı: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
  • Sayfa Sayıları: ss.652-662

Özet

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. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved.