title: 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.
authors.affiliation: Yeditepe University, Department of Genetics and Bioengineering, 26 Agustos Yerlesimi, 34755, Kayisdagi, Istanbul, Turkey.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Demir
authors.forename: Nese
authors.initials: N
authors.lastname: Aysit
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Onder
authors.forename: Nezaket
authors.initials: N
authors.lastname: Turkel
authors.forename: Gurkan
authors.initials: G
authors.lastname: Ozturk
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Sharrocks
authors.forename: Isil Aksan
authors.initials: IA
authors.lastname: Kurnaz
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000502:physiology; D002470:Cell Survival; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D016716:PC12 Cells; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*; D050807:ets-Domain Protein Elk-1 / Q000502:physiology*
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C526473:Smn1 protein, rat; D055533:Survival of Motor Neuron 1 Protein; D050807:ets-Domain Protein Elk-1; D020169:Caspases