Elsevier

Gene

Volume 294, Issues 1–2, 10 July 2002, Pages 1-12
Gene

Review
Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors

https://doi.org/10.1016/S0378-1119(02)00788-6Get rights and content

Abstract

Recent progress in the analysis of transcriptional regulation has revealed the presence of an exquisite functional network comprising the Maf and Cap ’n’ collar (CNC) families of regulatory proteins, many of which have been isolated. Among Maf factors, large Maf proteins are important in the regulation of embryonic development and cell differentiation, whereas small Maf proteins serve as obligatory heterodimeric partner molecules for members of the CNC family. Both Maf homodimers and CNC-small Maf heterodimers bind to the Maf recognition element (MARE). Since the MARE contains a consensus TRE sequence recognized by AP-1, Jun and Fos family members may act to compete or interfere with the function of CNC-small Maf heterodimers. Overall then, the quantitative balance of transcription factors interacting with the MARE determines its transcriptional activity. Many putative MARE-dependent target genes such as those induced by antioxidants and oxidative stress are under concerted regulation by the CNC family member Nrf2, as clearly proven by mouse germline mutagenesis. Since these genes represent a vital aspect of the cellular defense mechanism against oxidative stress, Nrf2-null mutant mice are highly sensitive to xenobiotic and oxidative insults. Deciphering the molecular basis of the regulatory network composed of Maf and CNC families of transcription factors will undoubtedly lead to a new paradigm for the cooperative function of transcription factors.

Section snippets

Isolation of Maf family proteins

The advent of ‘Maf-CNC biology’ arose from isolation of the v-maf oncogene, the transforming gene of avian retrovirus AS42, which causes musculoaponeurotic fibrosarcoma in chickens (Nishizawa et al., 1989). A distinctive feature of the v-Maf protein product of this oncogene is its basic leucine zipper (bZip) domain, the crystal structure of which has been determined in a GCN4 homodimer (Ellenberger et al., 1992) and in the Jun-Fos (AP-1) heterodimer (Glover and Harrison, 1995). The bZip domain

Nrf1, Nrf2, and Nrf3

Since the isolation of p45, the search for other NF-E2 (or NF-E2-type MARE) binding factors led to the identification of Nrf1, Nrf2, and Nrf3. All of these factors share the conserved CNC-like bZip motif and exploit small Maf proteins as obligatory heterodimeric partner molecules for binding to the MARE (Toki et al., 1997, Kobayashi et al., 1999). A probe containing the tandem MARE of the β-globin LCR was used to isolate Nrf1/lCR-F1 from a cDNA expression library (Chan et al., 1993, Caterina et

Nrf2 is a key regulator in the electrophilic counter-attack response

The study of transcriptional regulation through the MARE brought about a new paradigm in the field of molecular toxicology. Xenobiotic exposure provokes induction of detoxicating enzymes responsible for converting xenobiotics into their less harmful, more hydrophilic forms. Xenobiotics are detoxicated in two-steps: a phase I reaction followed by a phase II reaction. During phase I detoxication, the cytochrome P450 mono-oxygenase system catalyses the oxidation of xenobiotics to their

Abundance of small Maf proteins serves as a transcriptional switch

The CNC and Bach family transcription factors require small Maf partners in order to bind to the MARE sequence. Since small Mafs do not possess any canonical transactivation domain, small Maf homodimers function as transcriptional repressors. Thus, a deficiency in small Mafs would impair the function of CNC and Bach factors yet an excess of small Mafs is also predicted to increase small Maf homodimer formation and lead to repressed transcription. Indeed, when an increasing amount of MafK was

Structural basis of the unique DNA recognition mode of Maf family proteins

Transcription factors of the bZip family possess a basic region and a leucine zipper domain and include proteins such as Skn-1 (contains only a basic region), Nrf2, c-Jun, c-Fos, ATF-4, and Maf (Fig. 1). Maf proteins recognize 13 bp T-MAREs containing the TRE consensus (TGACTCA) or 14 bp C-MAREs containing the CRE consensus (TGACGTCA). In these MAREs, the core consensus motif is flanked on each side by three conserved residues: ‘TGC’ and ‘GCA’ at the 5′-end and 3′-end, respectively. Similarly,

Acknowledgements

This work was supported in part by JSPS, CREST, PROBRAIN and the Ministry of Education, Science, Sports and Culture of Japan.

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