MafA has strong cell transforming ability but is a weak transactivator

Abstract

The maf oncogene of the avian oncogenic retrovirus AS42 encodes a nuclear bZip protein, v-Maf, that recognizes sequences related to the AP-1 target site. The corresponding cellular protein, c-Maf belongs to a family of related bZip proteins together with MafA and MafB. In this paper, we compare the transactivation and cell transforming abilities of MafA and MafB along with two forms of the c-Maf protein. These proteins induce cellular transformation when expressed in chicken embryo fibroblasts. In reporter assays, MafA is a much less effective transactivator than the other Maf proteins, but unexpectedly shows the strongest activity in cell transformation. Chimeras of MafA and MafB correlate the strong cell transforming ability of MafA with its DNA-binding domain. The DNA-binding domain of MafA is also correlated with weak transactivation. Additional mutagenesis experiments show that transactivation and transformation by MafA are also controlled by phosphorylation of two conserved serine residues in the transactivation domain. Finally, we constructed MafAestrogen receptor fusion molecules that show tightly hormone-dependent cell transforming ability. These regulatable constructs permit a kinetic characterization of target gene responses and facilitate discrimination between direct and indirect targets.

The Minimal Transactivation Domain of the Basic Motif-Leucine Zipper Transcription Factor NRL Interacts with TATA-binding Protein

“…This hypothesis is consistent with the human mutation reports; 5 of the 6 mutations of NRL, so far reported in patients with autosomal dominant retinitis pigmentosa, are at residues Ser-50 and Pro-51 (27)(28)(29), and the S50T mutation was shown to enhance the ability of NRL to transactivate the rhodopsin promoter in the presence of CRX (27). In addition, the identification of phosphorylation and subsequent mutation analysis of residue Ser-65 in MafA, the homologous residue of Ser-50 in NRL, further supports this hypothesis (58,59). To investigate it further, we altered individual serine and threonine residues (Ser-38, Ser-41, Thr-42, Ser-45, Ser-46, Ser-50, Thr-52, and Ser-54) to alanine and examined their effect on the transactivation ability of NRL using the rhodopsin promoter activity assay similar to that reported earlier (27).…”

CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element

“…Maf family members have been reported to act as both transcriptional activators or repressors and their characterized phosphorylation sites can serve to either stimulate or inhibit function (Nishizawa et al, 2003,Ochi et al, 2003. To determine if the c-Maf point mutants (S15A, S70A, and S15A/S70A) display cell type-dependent functional variability, we assessed their transactivation capacity in endothelial and liver epithelial cell lines (153/luc, Fig.…”

Reexpression of oncoprotein MafB in proliferative β-cells and Men1 insulinomas in mouse

“…Although their oncogenic role appears to depend on cell type and tissue (Pouponnot et al, 2006;Rocques et al, 2007), several reports including their translocation in human multiple myeloma (Chesi et al, 1998) have firmly established the large Maf family members, MafA, MafB and c-Maf, as bona fide protooncogenes (Eyche`ne et al, 2008). It was shown that Maf proteins can transform primary cells (Nishizawa et al, 2003;Pouponnot et al, 2006). Their oncogenic activity was also demonstrated in multiple myeloma cell lines (Hurt et al, 2004) and in mice (Morito et al, 2006(Morito et al, , 2011.…”