Negative regulatory proteins in a cytokine signaling play a critical role in restricting unwanted excess activation of the signaling pathway. At the same time, negative regulatory proteins need to be removed rapidly from cells to respond properly to the next incoming signal. A nuclear I kappa B protein called I kappa BNS is known to inhibit a subset of NF-kappa B target genes upon its expression by NE-kappa B activation. Here, we show a mechanism to control the stability of mI kappa BNS which might be important for cells to prepare the next round signaling. We found that mI kappa BNS is a short-lived protein of which the stability is controlled by proteasome, independent of ubiquitylation process. We identified that the N-terminal PEST sequence in mI kappa BNS was critical for the regulation of stability. (C) 2014 Elsevier Inc. All rights reserved.