Gene name - Jun-related antigen
Synonyms - DJun
Cytological map position - 46E
Function - transcription factor
Symbol - Jra
Genetic map position - 2-
Classification - basic leucine zipper
Cellular location - nuclear
Mammalian JUN is a transcription factor and oncogene. It is activated through RAS/MAPK-mediated phosphorylation. In mammalian cells JUN interacts with FOS, another basic leucine zipper protein (See Drosophila Fos-related antigen). AP-1 is a FOS-JUN heterodimer that serve to activate genes involved in neural function and the immune response. Multiple FOS and JUN proteins are found in mammals. Most of the genes encoding AP-1 components behave as "immediate early" genes, that is, genes whose transcription is rapidly induced following cell stimuation, independent of de novo protein synthesis. JUN transcriptional activity is regulated by phosphorylation carried out by JUN kinase, which in turn is activated by phosphorylation cascades initiated by growth factor signals (Karin, 1995).
In the Drosophila eye, Jun-related antigen is activated through the Boss-Sevenless pathway. The ligand Boss is secreted by R8 photoreceptor cells and triggers a phosphorylation cascade through the receptor tyrosine kinase Sevenless. Sevenless is found on the surface of cells for only a limited time restricting the number of cells that can turn into photoreceptors (Treier, 1995). Similarly, Jun is upregulated on either side of the morphogenetic furrow (Bohmann, 1994), and thus acts in only a restricted number of cells. Sevenless signaling activates the RAS-MAPK pathway. Rolled MAPK in turn activates JRA, again by means of phosphorylation.
Jun-related antigen cooperates with the ETS domain protein Pointed to induce R7 fate in the developing eye. Jun-related antigen and Pointed are presumed to act on common targets to promote the R7 photoreceptor fate. After a decade of research, a role for Jun-related antigen has been found in only one phase of differentiation, the determination of the R7 photoreceptor. Where else is JUN involved in cell differentiation? The next decade may reveal more targets, following clues provided by an examination of the Jra promoter.
As in mammalian systems, Jun-related antigen is activated by AP-1, or said another way, it is subject to autoregulation. In addition, a cyclic AMP response element (CRE) is found, suggesting that Jra is responsive to regulation by CREB, the cyclic AMP response element binding protein. In fact, deletion of the CRE reduces by half the Jra promoter activity. The involvement of cAMP and CREB in Jra transcription suggests Jra is involved in memory. An additional three ecdysone response elements are found in an upstream region. Since ecdysone regulates molting this suggests that Jra is regulated during molting (Wang, 1994). This could implicate Jra in formation of adult neural structures.
The Drosophila homolog of c-Jun regulates epithelial cell shape changes during the process of dorsal closure in mid-embryogenesis. A mutation in Fra shows defects in dorsal closure and also interacts with mutations in Jra. Like Jra mutations, Fra null alleles completely block shape changes that normally occur in the leading edge of the lateral epithelium during dorsal closure. In dorsal closure, Fra cooperates with Jra by regulating the expression of dpp; Dpp acts as a relay signal that triggers cell shape changes and Fra expression in neighboring cells (Riesgo-Escovar, 1997b).
In vertebrates, c-Jun and c-Fos activities are regulated at various levels. Whereas c-Jun is widely expressed at low levels and activated primarily by NH2-terminal phosphorylation by JNKs, c-fos expression is dynamic and activated in response to various extracellular stimuli. A similar dichotomy of Jra and Fra regulation occurs in Drosophila: Jra is widely expressed during embryogenesis and is phosphorylated by DJNK (Basket), whereas Fra expression is dynamic. There is strong expression of Fra in leading edge cells and cells of the lateral epithelium. Expression of Fra in the lateral epithelium is reduced in thick veins and punt mutant embryos but is still detectable in the leading edge. Therefore, not only does Fra control expression of dpp in the leading edge, but in a reciprocal manner, Fra expression is dependent on Dpp function in cells of the lateral epithelium. Similarly, in late embryos, Fra expression in the endoderm depends on dpp expression in the overlying visceral mesoderm. Activation of the Dpp signaling pathway is indeed sufficient to activate Fra expression. Ectopic expression of an activated Dpp receptor (Thickveins) in a segmental pattern results in a corresponding pattern for Fra expression. It is concluded that Fra may be required in all ectodermal cells in order to activate target genes required for cell shape changes (Riesgo-Escovar, 1997b).
In addition to the joint requirement of Fra and Jra during dorsal closure, Fra functions independently of Jra during embryogenesis. Early dpp expression on the dorsal side of embryos induces expression of several genes, including race, which encodes a protein with homology to angiotensin-converting enzyme in the amnioserosa. The race cis-acting sequences required for dpp-mediated expression contain AP-1 binding sites. Consistent with Fra-mediated direct activation of race through these AP-1 sites, race expression in the amnioserosa is abolished in Fra mutants. In contrast, race expression is normal in Jra or basket mutant embryos. This early Jra-independent function of Fra may be mediated by a Fra homodimer. During wound healing in vertebrates (a process that exhibits parallels with dorsal closure), TGF-beta induces c-fos expression and AP-1 activity. The reciprocal regulatory relation between Fra and dpp in Drosophila appears to be conserved in mammalian cells. In mammalian myeloid cells, induction of c-jun and c-fos by serum or oncogenic v-src results in expression of TGF-beta1 by direction activation of TGF-beta1 transcription by AP1. TGF-beta induces AP-1 activity in keratinocytes during wound healing. These findings demonstrate common and distinct roles for Fra and Jra during embryogenesis and suggest a conserved link between AP-1 (activating protein-1) and TGF-beta (transforming growth factor-beta) signaling during epithelial cell shape changes (Riesgo-Escovar, 1997b).
Exons - one
The JRA protein is 58% homologous to human proto-oncogene cJUN and has high homology in both the basic DNA binding and leucine zipper regions (Perkins, 1988, Zhang, 1990 and Wang, 1994).
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