Opposing roles of Elk-1 and its brain-specific isoform, short Elk-1, in nerve growth factor-induced PC12 differentiation

J Biol Chem. 2001 Feb 16;276(7):5189-96. doi: 10.1074/jbc.M006678200. Epub 2000 Oct 24.


The ternary complex factor Elk-1, a major nuclear target of extracellular signal-regulated kinases, is a strong transactivator of serum-responsive element (SRE) driven gene expression. We report here that mature brain neurons and nerve growth factor (NGF)-differentiated PC12 cells also express a second, smaller isoform of Elk-1, short Elk-1 (sElk-1). sElk-1 arises from an internal translation start site in the Elk-1 sequence, which generates a protein lacking the first 54 amino acids of the DNA-binding domain. This deletion severely compromises the ability of sElk-1 to form complexes with serum response factor on the SRE in vitro and to activate SRE reporter genes in the presence of activated Ras. Instead, sElk, but not a mutant that cannot be phosphorylated, inhibits transactivation driven by Elk-1. More pertinent to the neuronal-specific expression of sElk-1, we show it plays an opposite role to Elk-1 in potentiating NGF-driven PC12 neuronal differentiation. Overexpression of sElk-1 but not Elk-1 increases neurite extension, an effect critically linked to its phosphorylation. Interestingly, in the presence of sElk-1, Elk-1 loses its strictly nuclear localization to resemble the nuclear/cytoplasm pattern observed in the mature brain. This is blocked by mutating a normally cryptic nuclear export signal in Elk-1. These data provide new insights into molecular events underlying neuronal differentiation of PC12 cells mediated by the NGF-ERK signaling cascade.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Antibodies / immunology
  • Brain / metabolism*
  • Cell Differentiation
  • Cell Nucleus / metabolism
  • Codon, Initiator
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / physiology
  • Male
  • Nerve Growth Factor / pharmacology*
  • Neurons / cytology*
  • Neurons / metabolism
  • PC12 Cells
  • Phenotype
  • Protein Isoforms / genetics
  • Protein Isoforms / immunology
  • Protein Isoforms / physiology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology
  • Proto-Oncogene Proteins / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factors / genetics
  • Transcription Factors / immunology
  • Transcription Factors / physiology
  • Transcriptional Activation
  • ets-Domain Protein Elk-1


  • Antibodies
  • Codon, Initiator
  • DNA-Binding Proteins
  • Elk1 protein, rat
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • Nerve Growth Factor