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The transcription factor Foxo, which is inhibited by the insulin/IGF signaling (IIS), extends life span in conditions of low IIS activity but life span can also be increased by activating the stress-responsive Jun-N-terminal kinase (JNK) pathway. A model to explain the effects of stress and nutrition on longevity provides can be provided by the convergence of JNK signaling and IIS on Foxo.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.02.030 Byline: Meng C. Wang (1), Dirk Bohmann (1), Heinrich Jasper (1) Abstract: Aging of a eukaryotic organism is affected by its nutrition state and by its ability to prevent or repair oxidative damage. Consequently, signal transduction systems that control metabolism and oxidative stress responses influence life span. When nutrients are abundant, the insulin/IGF signaling (IIS) pathway promotes growth and energy storage but shortens life span. The transcription factor Foxo, which is inhibited by IIS, extends life span in conditions of low IIS activity. Life span can also be increased by activating the stress-responsive Jun-N-terminal kinase (JNK) pathway. Here we show that JNK requires Foxo to extend life span in Drosophila. JNK antagonizes IIS, causing nuclear localization of Foxo and inducing its targets, including growth control and stress defense genes. JNK and Foxo also restrict IIS activity systemically by repressing IIS ligand expression in neuroendocrine cells. The convergence of JNK signaling and IIS on Foxo provides a model to explain the effects of stress and nutrition on longevity. Author Affiliation: (1) Department of Biomedical Genetics, The Aab Institute of Biomedical Sciences, University of Rochester Medical Center, 601 Elmwood Avenue, Box 633, Rochester, New York 14642 Article History: Received 8 November 2004; Revised 20 January 2005; Accepted 28 February 2005 Article Note: (miscellaneous) Published online: March 24, 2005

Drosophila Fos has been found to mediate ERK and JNK signals through distinct phosphorylation sites. Fos can mediate ERK signaling in wing vein formation and photoreceptor differentiation.

The interaction of JUN and Pointed (PNT) protein induces the formation of R7 photoreceptor neurons in the Drosophila eye. The activity of JUN and PNT on the phyllopod (phyl) gene, a transcriptional target of the RAS pathway during R7 differentiation, induces the differentiation. Targeting the proteins to one promoter results in cooperative binding of JUN to the ETS domain of PNT. The binding is inhibited by YAN, which suppresses R7 differentiation, and phyl.

Neuronal development in the Drosophila melanogaster eye requires the Jun downstream of the sevenless/ras signalling pathway. The fate of neuronal photoreceptors in the eye of D. melanogaster is determined by the expression of the Jun, a transcription factor, in the imaginal disc of the eye. The dose-dependent loss of photoreceptors in adult flies is caused by the expression of various negative forms of Jun in the photoreceptor precursor cells. But the same localized overexpression of the Jun stimulates the differentiation of the photoreceptor cells.

An investigation of the ubiquitin-dependent proteolysis system in the breakdown of c-Jun, a signal transducing transcription factor, reveals that only c-Jun is capable of being efficiently multiubiquitinated while its transforming counterpart, v-Jun, cannot be multiubiquitinated. The investigation involves use of a new in-vivo assay, which requires a molecularly-tagged ubiquitin and the proteins of c-Jun. The stability of v-Jun, as determined from mutagenesis experiments, reveals that the absence of 27 amino acids causes its stability.

Abstract Background The transcription factor AP-1 positively controls synaptic plasticity at the Drosophila neuromuscular junction. Although in motor neurons, JNK has been shown to activate AP-1, a positive regulator of growth and strength at the larval NMJ, the consequences of JNK activation are poorly studied. In addition, the downstream transcriptional targets of JNK and AP-1 signaling in the Drosophila nervous system have yet to be identified. Here, we further investigated the role of JNK signaling at this model synapse employing an activated form of JNK-kinase; and using Serial Analysis of Gene Expression and oligonucleotide microarrays, searched for candidate early targets of JNK or AP-1 dependent transcription in neurons. Results Temporally-controlled JNK induction in postembryonic motor neurons triggers synaptic growth at the NMJ indicating a role in developmental plasticity rather than synaptogenesis. An unexpected observation that JNK activation also causes a reduction in transmitter release is inconsistent with JNK functioning solely through AP-1 and suggests an additional, yet-unidentified pathway for JNK signaling in motor neurons. SAGE profiling of mRNA expression helps define the neural transcriptome in Drosophila. Though many putative AP-1 and JNK target genes arose from the genomic screens, few were confirmed in subsequent validation experiments. One potentially important neuronal AP-1 target discovered, CG6044, was previously implicated in olfactory associative memory. In addition, 5 mRNAs regulated by RU486, a steroid used to trigger conditional gene expression were identified. Conclusion This study demonstrates a novel role for JNK signaling at the larval neuromuscular junction and provides a quantitative profile of gene transcription in Drosophila neurons. While identifying potential JNK/AP-1 targets it reveals the limitations of genome-wide analyses using complex tissues like the whole brain.

Genetic and molecular evidence that the histone acetyltransferase (HAT) Chameau and the histone deacetylase DRpd3 act as antagonistic cofactors of DJun and DFos to modulate Jun N-terminal kinase (JNK)-dependent transcription during thorax metamorphosis and JNK-induced apoptosis in Drosophila. It is demonstrated in cultured cells that DFos phosphorylation mediated by JNK signaling plays a central role in coordinating the dynamics of Chameau and DRpd3 recruitment and function at AP-1-responsive promoters.