PT  - JOURNAL ARTICLE
AU  - Lu Qiu
AU  - Meng Wang
AU  - Yuping Zhu
AU  - Yuancai Xiang
AU  - Yiguo Zhang
TI  - A naturally-occurring dominant-negative competitor of Keap1 against its inhibition of Nrf2
AID  - 10.1101/286997
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 286997
4099  - http://biorxiv.org/content/early/2018/03/23/286997.short
4100  - http://biorxiv.org/content/early/2018/03/23/286997.full
AB  - Transcription factor Nrf2 is a master regulator of antioxidant and/or electrophile response elements (AREs/EpREs)driven genes involved in homeostasis, detoxification and adaptation to various stresses. The cytoprotective activity of Nrf2, though being oppositely involved in both cancer prevention and progression, is critically controlled by Keap1 (Kelch-like ECH-associated protein 1) as an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, that is a key sensor for oxidative and electrophilic stresses. Now, we first report a novel naturally-occurring mutant of Keap1, designated Keap1ΔC, which lacks most of its C-terminal Nrf2-interacting domain essential for inhibition of the CNC-bZIP factor. This mutant Keap1ΔC is yielded by translation from an alternatively mRNA-spliced variant lacking the fourth and fifth exons, but their coding sequences are retained in the wild-type Keap1 locus (with no genomic deletions). Although this variant was found primarily in the human highly-metastatic hepatoma (MHCC97H) cells, it was widely expressed at very lower levels in all other cell lines examined. No matter whether Keap1ΔC retains less or no ability to inhibit Nrf2, it functions as a dominant-negative competitor of Keap1 against its inhibition of Nrf2-target genes. This is due to its antagonist effect on Keap1-mediated turnover of Nrf2 protein.