Molecular Cloning and Functional Characterization of a New Cap'n' Collar Family Transcription Factor Nrf3

Abstract

The NF-E2-binding sites or Maf recognition elements (MARE) are essential cis-acting elements in the regulatory regions of erythroid-specific genes recognized by the erythroid transcription factor NF-E2, composed of p45 and MafK. Recently, two p45-related factors Nrf1 and Nrf2 were isolated, and they are now collectively grouped as the Cap'n' collar (CNC) family. CNC factors bind to MARE through heterodimer formation with small Maf proteins. We report here the identification and characterization of a novel CNC factor, Nrf3, encoding a predicted 73-kDa protein with a basic regionleucine zipper domain highly homologous to those of other CNC proteins. In vitro and in vivo analyses showed that Nrf3 can heterodimerize with MafK and that this complex binds to the MARE in the chicken ␤-globin enhancer and can activate transcription. Nrf3 mRNA is highly expressed in human placenta and B cell and monocyte lineage. Chromosomal localization of human Nrf3 is 7p14 -15, which lies near the hoxA gene locus. As the genetic loci of p45, nrf1, and nrf2 have been mapped close to those of hoxC, hoxB, and hoxD, respectively, the present study strongly argues for the idea that a single ancestral gene for the CNC family members may have been localized near the ancestral Hox cluster and have diverged to give rise to four closely related CNC factors through chromosome duplication.

c-Maf negatively regulates ARE-mediated detoxifying enzyme genes expression and anti-oxidant induction

“…The various genes ARE bind to a complex of nuclear proteins from cells of different origins (Dhakshinamoorthy et al, Li and Jaiswal, 1992;Venugopal and Jaiswal, 1996;Liu and Pickett, 1996;Vasliou et al, 1995;Yoshioka et al, 1995;Venugopal and Jaiswal, 1998;Kwong et al, 1999;Alam et al, 1999). Recently, Nrf3, a third member of the Nrf family of transcription factors was cloned and sequenced (Kobayashi et al, 1999). However, the role of Nrf3 in the regulation of ARE-mediated expression and induction of detoxifying enzyme genes remains unknown.…”

Long range interaction of cis‐DNA elements mediated by architectural transcription factor Bach1

“…MAREs can be bound by various heterodimers composed of Maf-related proteins and Cap'n'collar (CNC)-related bZip proteins including NF-E2 p45, Nrf1, Nrf2, Nrf3, Bach1 and Bach2 (Andrews et al 1993;Igarashi et al 1994;Oyake et al 1996;Toki et al 1997;Kobayashi et al 1999). Among these proteins, Bach1 and Bach2 are unique in that they repress transcription by binding to MAREs Oyake et al 1996), a characteristic not uncommon to other BTB/POZ domain transcription factors (e.g.…”

“…A variety of basic leucine zipper (bZip) proteins (e.g. p45 NF-E2, Nrf1, Nrf2, Nrf3 and Bach1) can interact with MAREs as heterodimers with the small Maf proteins (MafK, MafG, or MafF;Andrews et al 1993;Igarashi et al 1994;Oyake et al 1996;Toki et al 1997;Kobayashi et al 1999 Among these MARE-interacting factors, Bach1 is unique, in that it possesses a BTB/POZ domain. Bach1 forms a multivalent DNA binding complex (Igarashi et al 1998), raising the possibility that it could act as an architectural component that is simultaneously able to crosslink multiple MAREs.…”

Cloning and expression of human B cell-specific transcription factor BACH2 mapped to chromosome 6q15

“…The small Maf proteins form heterodimers with a family of bZip proteins that show remarkable homology to two invertebrate proteins, CNC and skn-1, which regulate embryonic development in Drosophila melanogaster and Caenorhabditis elegans, respectively (Mohler et al, 1991(Mohler et al, , 1995Bowerman et al, 1992). This family of factors, referred to as the CNC family, include p45 NF-E2, Nrf1/LCR-F1/TCF-11, Nrf2, and Nrf3, all of which are similar in the bZip domain and form heterodimers with small Maf proteins (Andrews et al, 1993a,b;Chan et al, 1993a,b;Ney et al, 1993;Caterina et al, 1994;Moi et al, 1994;Igarashi et al, 1994Igarashi et al, , 1995Marini et al, 1997;Johnsen et al, 1996;Toki et al, 1997;Kobayashi et al, 1999). Gene targeting has revealed distinct roles for several CNC family members in mammalian gene regulation.…”