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Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway.

Motohashi H., Katsuoka F., Engel J.D., Yamamoto M.

The small Maf proteins, MafF, MafG, and MafK, possess a leucine zipper (Zip) domain that is required for homodimer or heterodimer complex formation with other bZip transcription factors. In this study we sought to determine the identity of the specific constituent that collaboratively interacts with Nrf2 to bind to the Maf recognition element in vivo. Studies in vitro suggested that Nrf2 forms heterodimers with small Maf proteins and then bind to Maf recognition elements, but the bona fide partner molecules supporting Nrf2 activity in vivo have not been definitively identified. Nrf2 activity is usually suppressed by a cytoplasmic repressor, Keap1, so disruption of the keap1 gene causes constitutive activation of Nrf2. Nrf2 hyperactivity results in hyperproliferation of keratinocytes in the esophagus and forestomach leading to perinatal lethality. However, simultaneous disruption of nrf2 rescued keap1-null mice from the lethality. We exploited this system to investigate whether small Mafs are required for Nrf2 function. We generated keap1 and small maf compound mutant mice and examined whether keratinocyte abnormalities persisted in these animals. The data show that loss of mafG and mafF in the keap1-null mice reversed the lethal keratinocyte dysfunction and rescued the keap1-null mutant mice from perinatal lethality. This rescue phenotype of mafG::mafF::keap1 triple compound mutant mice phenocopies that of the nrf2::keap1 compound mutant mice, indicating that the small Maf proteins MafG and MafF must functionally cooperate with Nrf2 in vivo.

Proc. Natl. Acad. Sci. U.S.A. 101:6379-6384(2004) [PubMed] [Europe PMC]

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