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Citation

  • Authors: Chen, F. Y., Huang, M. Y., Lin, Y. M., Ho, C. H., Lin, S. Y., Chen, H. Y., Hung, M. C., Chen, R. H.
  • Year: 2019
  • Journal: J Cell Biol
  • Applications: in vivo / DNA / in vivo-jetPEI

Method

For BIKDD gene therapy protocol, 5-wk-old female BALB/cAnN.Cg-Foxnlnu/ CrlNarl nude mice were inoculated in the mammary fat pad with 2 × 106 Hs578T cells. 28 d later, DMSO or STF-083010 (40 mg/kg) was intraperitoneally administrated every 3–4 d. Control vector or VISA-BIKDD (0.75 mg/kg) was first incubated with the in vivo jetPEI delivery reagent for 15 min, and then the complex was intratumorally injected every 7 d starting at day 28.

Abstract

The BH3-only pro-apoptotic protein BIK is regulated by the ubiquitin-proteasome system. However, the mechanism of this regulation and its physiological functions remain elusive. Here, we identify Cul5-ASB11 as the E3 ligase targeting BIK for ubiquitination and degradation. ER stress leads to the activation of ASB11 by XBP1s during the adaptive phase of the unfolded protein response, which stimulates BIK ubiquitination, interaction with p97/VCP, and proteolysis. This mechanism of BIK degradation contributes to ER stress adaptation by promoting cell survival. Conversely, genotoxic agents down-regulate this IRE1alpha-XBP1s-ASB11 axis and stabilize BIK, which contributes in part to the apoptotic response to DNA damage. We show that blockade of this BIK degradation pathway by an IRE1alpha inhibitor can stabilize a BIK active mutant and increase its anti-tumor activity. Our study reveals that different cellular stresses regulate BIK ubiquitination by ASB11 in opposing directions, which determines whether or not cells survive, and that blocking BIK degradation has the potential to be used as an anti-cancer strategy.

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