Expression and function of the JunD transcription Factors: JunD-FL and Delta-JunD

JunD is a member of the Jun family of basic region leucine zipper proteins that can form homodimers or form heterodimers with other Jun family members (c-Jun and JunB) or Fos family members (c-Fos, FosB, Fra-1, Fra-2). Collectively, these dimer combinations make up the Activator Protein-1 (AP-1) transcription factor. AP-1 binds to the TPA-response element, TGAG/CTCA, within the promoter of a wide-range of genes, many of which are important for cell growth regulation. JunD functions as a negative regulator of transformed cell growth and antagonizes transformation by the ras oncogene. JunD also functions to protect cells from premature senescence and apoptosis.

The junD gene, like the other jun genes, is intronless and generates a single mRNA. However, we have found that the JunD mRNA generates two predominant JunD protein isoforms through alternative translational initiation. The larger JunD isoform, JunD-FL (39 kD) is generated by translational initiation at the first AUG downstream of the m7-G cap, and the smaller JunD isoform, AJunD (34 kD), is generated by translational initiation at the third AUG codon from the m7-G cap. These AUG codons are in-frame, making JunD-FL a 48-amino acid N-terminal extension of ÄJunD. We have also identified four other potential translational initiation events that occur at both AUG and non-AUG start codons within the JunD mRNA, suggesting that there are six peptides generated from the JunD mRNA.

JunD-FL and AJunD function differentially within the cell. Both JunD isoforms bind to Jun-N-terminal kinases (JNKs), but JNKs more potently stimulate transactivation of JunD-FL in vitro. In addition, JunD-FL interacts with the Menin tumor suppressor protein. Menin inhibits transcriptional activity of JunD-FL in vitro, but does not bind to or inhibit ÄJunD transcriptional activity. We have identified several putative target genes of JunD-FL and ÄJunD, including the nuclear orphan receptor nur77, which is involved in cell growth arrest and cellular apoptosis. We found that Nur77 is positively regulated by JunD-FL and ÄJunD in a similar manner but is negatively regulated by c-Jun.