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The novel Nrf2-interacting factor KAP1 regulates susceptibility to oxidative stress by promoting the Nrf2-mediated cytoprotective response.

The transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) co-ordinately regulates ARE (antioxidant-response element)-mediated induction of cytoprotective genes in response to electrophiles and oxidative stress; however, the molecular mechanism controlling Nrf2-dependent gene expression is not fully understood. To identify factors that regulate Nrf2-dependent transcription, we searched for proteins that interact with the Nrf2-NT (N-terminal Nrf2 transactivation domain) by affinity purification from HeLa nuclear extracts. In the present study, we identified KAP1 [KRAB (Kr├╝ppel-associated box)-associated protein 1] as a novel Nrf2-NT-interacting protein. Pull-down analysis confirmed the interaction between KAP1 and Nrf2 in cultured cells and demonstrated that the N-terminal region of KAP1 binds to Nrf2-NT in vitro. Reporter assays showed that KAP1 facilitates Nrf2 transactivation activity in a dose-dependent manner. Furthermore, the induction of the Nrf2-dependent expression of HO-1 (haem oxygenase-1) and NQO1 [NAD(P)H quinone oxidoreductase 1] by DEM (diethyl maleate) was attenuated by KAP1 knockdown in NIH 3T3 fibroblasts. This finding established that KAP1 acts as a positive regulator of Nrf2. Although Nrf2 nuclear accumulation was unaffected by KAP1 knockdown, the ability of Nrf2 to bind to the regulatory region of HO-1 and NQO1 was reduced. Moreover, KAP1 knockdown enhanced the sensitivity of NIH 3T3 cells to tert-butylhydroquinone, H2O2 and diamide. These results support our contention that KAP1 participates in the oxidative stress response by maximizing Nrf2-dependent transcription.

Pubmed ID: 21382013


  • Maruyama A
  • Nishikawa K
  • Kawatani Y
  • Mimura J
  • Hosoya T
  • Harada N
  • Yamamato M
  • Itoh K


The Biochemical journal

Publication Data

June 1, 2011

Associated Grants


Mesh Terms

  • Animals
  • Cells, Cultured
  • Cytoprotection
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Knockout
  • NF-E2-Related Factor 2
  • NIH 3T3 Cells
  • Oxidative Stress
  • Protein Binding
  • Repressor Proteins