The maf oncogene was originally identified as the transduced cellular component of the acutely transforming avian retrovirus, AS42. The murine family of basic/zipper transcription factors that are structurally related to the original v-Maf oncoprotein fall into three categories, designated the large or small Maf family members and the CNC proteins. The large Maf proteins (c-Maf, NRL and MafB) have a typical bZip protein structure (including trans-activation domains), while the small Maf proteins (MafK, MafF and MafG) consist essentially of only a leucine zipper and basic DNA binding domain. In contrast to previous studies which erroneously concluded that the small Maf proteins are present in all animal tissues, these investigators have recently found that MafK and MafG are both highly tissue-restricted in their expression patterns during murine embryogenesis. The small Maf proteins heterodimerize with both large Maf molecules as well as five currently known CNC (Cap-N- Collar) family members (p45 NF-E2, Nrfl, Nrf2, Bachl and Bach2) to bind to specific regulatory sites in DNA. CNC homodimers typically bind poorly to Maf recognition elements (MAREs or NF-E2 sites), while heterodimers consisting of a small Maf protein and a CNC family partner generate trans-activating DNA binding proteins. In contrast to the inactivity of CNC homodimers, homo- or heterodimer formation between small Maf family proteins leads to formation of powerful repressors. Thus small Maf proteins acting alone negatively regulate gene expression, while when acting in collusion with a large Maf or CNC partner, they activate transcription. It is proposed to investigate the developmental genetics of the small maf family genes through execution of four specific aims in this study: First, the investigators will analyze the individual and combinatorial genetic and developmental effects of germ line ablation of the three small maf genes and determine their embryonic and adult developmental expression profiles as well as their null mutant phenotypes; second, they will generate mice which express only single small Maf proteins to test a newly emerging evolutionary hypothesis; third, they will map and then clone a recently identified lethal genetic modifier of mafG; and fourth, they will isolate and then functionally characterize murine YAC recombinants encoding the small maf genes, using them for in vivo rescue of specific small maf loss of function mutations and phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080088-02
Application #
6124669
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Okano, Paul
Project Start
1998-12-10
Project End
2003-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
2
Fiscal Year
2000
Total Cost
$273,108
Indirect Cost
Name
Northwestern University at Chicago
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
Evanston
State
IL
Country
United States
Zip Code
60201
Moriguchi, Takashi; Hamada, Michito; Morito, Naoki et al. (2006) MafB is essential for renal development and F4/80 expression in macrophages. Mol Cell Biol 26:5715-27
Motohashi, Hozumi; Katsuoka, Fumiki; Miyoshi, Chika et al. (2006) MafG sumoylation is required for active transcriptional repression. Mol Cell Biol 26:4652-63
Katsuoka, Fumiki; Motohashi, Hozumi; Engel, James Douglas et al. (2005) Nrf2 transcriptionally activates the mafG gene through an antioxidant response element. J Biol Chem 280:4483-90
Zhang, Chuan; Moriguchi, Takashi; Kajihara, Miwako et al. (2005) MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol 25:4969-76
Motohashi, Hozumi; Katsuoka, Fumiki; Engel, James Douglas et al. (2004) Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway. Proc Natl Acad Sci U S A 101:6379-84
Katsuoka, Fumiki; Motohashi, Hozumi; Tamagawa, Yuna et al. (2003) Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response. Mol Cell Biol 23:1163-74
Onodera, K; Shavit, J A; Motohashi, H et al. (2000) Perinatal synthetic lethality and hematopoietic defects in compound mafG::mafK mutant mice. EMBO J 19:1335-45
Katsuoka, F; Motohashi, H; Onodera, K et al. (2000) One enhancer mediates mafK transcriptional activation in both hematopoietic and cardiac muscle cells. EMBO J 19:2980-91
Motohashi, H; Katsuoka, F; Shavit, J A et al. (2000) Positive or negative MARE-dependent transcriptional regulation is determined by the abundance of small Maf proteins. Cell 103:865-75
Itoh, K; Wakabayashi, N; Katoh, Y et al. (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76-86

Showing the most recent 10 out of 11 publications