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

被引:72
作者
Vanhoutte, P
Nissen, JL
Brugg, B
Della Gaspera, B
Besson, MJ
Hipskind, RA
Caboche, J [1 ]
机构
[1] Univ Paris 06, Inst Neurosci, Lab Neurochim Anat, CNRS,UMR 7624, F-75005 Paris, France
[2] Univ Paris 06, Inst Neurosci, Lab Dev & Vieillissement SNC, CNRS,UMR 7624, F-75005 Paris, France
[3] Univ Paris 06, Inst Neurosci, Mol Neurogenet Lab, CNRS,UMR 7624, F-75005 Paris, France
[4] CNRS, IFR 24, UMR 5535, Inst Genet Mol, F-34293 Montpellier 5, France
关键词
D O I
10.1074/jbc.M006678200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:5189 / 5196
页数:8
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