The major mRNA-associated protein YBA is a potent 5 ' cap-dependent mRNA stabilizer

mRNA silencing and storage play an important role in gene expression under diverse circumstances, such as throughout early metazoan development and in response to many types of environmental stress. Here we demonstrate that t he major mRNA-associated protein YB-1, also termed p50, is a potent cap-dep endent mRNA stabilizer. YB-1 addition or overexpression dramatically increa ses mRNA stability in vitro and in vivo, whereas YB-1 depletion results in accelerated mRNA decay. The cold shock domain of YB-1 is responsible for th e mRNA stabilizing activity, and a blocked mRNA 5' end is required for YB-1 -mediated stabilization. Significantly, exogenously added YB-1 destabilizes the interaction of the cap binding protein, elF4E, with the mRNA cap struc ture. Conversely, sequestration of eIF4E from the cap increases the associa tion of endogenous YB-1 with mRNA at or near the cap, and significantly enh ances mRNA stability. These data support a model whereby down-regulation of eIF4E activity or increasing the YB-1 mRNA binding activity or concentrati on in cells activates a general default pathway for mRNA stabilization.