Pereira CM, et al. (2005) IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation. J Biol Chem 280(31):28316-23
Abstract: Translational control directed by the eIF2alpha kinase GCN2 is important for coordinating gene expression programs in response to nutritional deprivation. The GCN2 stress response is conserved from yeast to mammals and is critical for resistance to nutritional deficiencies and for the control of feeding behaviors in rodents. IMPACT, a mouse imprinted gene, has sequence similarities with the yeast YIH1 protein, an inhibitor of GCN2. YIH1 competes with GCN2 for binding to a positive regulator, GCN1. In this work, we present evidence that IMPACT is the functional counterpart of YIH1. Overexpression of IMPACT in yeast lowers both basal and amino acid starvation-induced levels of phosphorylated eIF2alpha, as previously described for YIH1. Overexpression of IMPACT in mouse embryonic fibroblasts inhibits phosphorylation of eIF2alpha by GCN2 under leucine starvation, abolishing expression of its downstream target genes, ATF4(CREB-2) and CHOP(GADD153). IMPACT binds to the minimal yeast GCN1 segment required for the interaction with yeast GCN2 and YIH1, and to mouse native GCN1. At the protein level, IMPACT was detected mainly in the brain. IMPACT is abundant in the majority of hypothalamic neurons. Scattered neurons expressing this protein at higher levels were detected in other regions, such as the hippocampus and the piriform cortex. The abundance of IMPACT is inversely correlated with eIF2alpha(P) levels in different brain areas. These results taken together thus suggest that IMPACT ensures constant high levels of translation and low levels of ATF4 and CHOP in specific neuronal cells under amino acid starvation conditions.
|Status: Published||Type: Journal Article||PubMed ID: 15937339|
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