Cells damaged by environmental insults have to be repaired or eliminated to ensure tissue homeostasis in metazoans. Recent studies suggest that the balance between cell survival signals and pro-apoptotic stimuli controls the decision between cell repair and death. How these competing signals are integrated and interpreted to achieve accurate control over cell fate in vivo is incompletely understood. Here, we show that the Forkhead Box O transcription factor Foxo and the AP-1 transcription factor DFos are required downstream of Jun-N-terminal kinase signaling for the apoptotic response to UV-induced DNA damage in the developing Drosophila retina. Both transcription factors regulate the pro-apoptotic gene hid. Our results indicate that UV-induced apoptosis is repressed by receptor tyrosine kinase-mediated inactivation of Foxo. These data suggest that integrating stress and survival signals through Foxo drives the decision between cell death and repair of damaged cells in vivo.

Based on overexpression studies and target gene analyses, the transcription factor DNA replication-related element factor (DREF) has been proposed to regulate growth and replication in Drosophila melanogaster. Here we present loss-of-function experiments to analyze the contribution of DREF to these processes. RNA interference-mediated extinction of DREF function in vivo demonstrates a requirement for the protein for normal progression through the cell cycle and consequently for growth of imaginal discs and the derived adult organs. We show that DREF regulates the expression of genes that are required for the transition of imaginal disc cells through S phase. In conditions of suppressed apoptosis, DREF activation can cause overgrowth of developing organs. These data establish DREF as a global regulator of transcriptional programs that mediate cell proliferation and organ growth during animal development.The conversion from cellular self-renewal to differentiation, i.e., from a proliferating state to a postmitotic situation, is a fundamental step in the development of multicellular organisms. It is associated with major biochemical and metabolic transitions and coincides with global changes of gene expression. This event has to be regulated with exquisite precision, as small temporal or spatial deviations in switching from growth to differentiation phases of development can cause severe abnormalities. Furthermore, the regulation of genes that control the exit of the cell cycle and the subsequent cell fate decisions appears to be very tight, as exiting the cell cycle is a step that is rarely reversed in the adult. Failure to control growth arrest and terminal differentiation is the basis for malignant transformation and cancer. The termination of cell proliferation thus requires mechanisms that control many genes simultaneously in a coordinated, precise, and tight manner. In other situations where cells undergo major restructuring or changes of their physiology, as, for example, in the transition from a vegetatively growing bacterium to a spore or when germ line and soma separate during vertebrate development, such global changes are brought about by complex mechanisms that act at several levels of gene regulation. At the transcriptional level, events of this magnitude are mediated by enhancer binding transcription factors but also by changes of the general transcription machinery, such as sigma factors or TATA-binding protein variants (5,12,22).We have previously analyzed the changes of gene expression as cells of the developing Drosophila melanogaster eye transit from a pluripotent and mitotically active precursor state to terminally differentiated cell types that comprise the adult eye (10). These studies identified a population of genes that are selectively expressed in the dividing precursor cells located anterior to the morphogenetic furrow of the eye imaginal disc.Genes of this group encode proteins that are typical of a dividing and metabolically active cell, such as replication factors and protein synthesi...

The transcription factors of the Fos family have long been associated with the control of cell proliferation, although the molecular and cellular mechanisms that mediate this function are poorly understood. We investigated the contributions of Fos to the cell cycle and cell growth control using Drosophila imaginal discs as a genetically accessible system. The RNA interference-mediated inhibition of Fos in proliferating cells of the wing and eye discs resulted in a specific defect in the G 2 -to-M-phase transition, while cell growth remained unimpaired, resulting in a marked reduction in organ size. Consistent with the conclusion that Fos is required for mitosis, we identified cyclin B as a direct transcriptional target of Fos in Drosophila melanogaster, with Fos binding to a region upstream of the cyclin B gene in vivo and cyclin B mRNA being specifically reduced under Fos loss-of-function conditions.The Fos family of leucine zipper transcription factors in mammals is comprised of four members, the proto-oncogene product c-Fos and FosB, Fra1, and Fra2. A variety of partly redundant functions have been ascribed to these different proteins, and as a family, they have been implicated in the regulation of multiple cellular processes ranging from growth and proliferation to stress response and apoptosis (9,10,26,30). The ability of v-fos, the c-fos-derived retroviral oncogene, to transform avian and murine cells and the finding that the stimulation of quiescent cells with growth factors can rapidly induce c-fos gene expression have led to the suggestion that Fos proteins might regulate cell proliferation (5, 18). This notion was further supported by the finding that the microinjection of anti-Fos family antibodies into proliferating cells interfered with normal cell cycle progression (13). Another line of evidence in support of the idea that Fos might control cell proliferation came from genetic studies of mammalian systems. Murine fibroblasts deficient for both the c-fos and the fosB loci, but not the corresponding single mutants, showed impaired cell cycle progression (2). In addition to a potential role for Fos in the regulation of cell proliferation, this finding suggests functional redundancy among different mammalian Fos family members.When c-Fos was ectopically expressed in transgenic mice, defects in bone morphogenesis ensued, and osteosarcomas formed due to the transformation of osteoblasts (7,24,25). Recent studies confirmed that AP-1 transcription factors are also associated with osteosarcomas in humans (21). In spite of the many indirect lines of evidence that link Fos to the control of cell proliferation and implicate it in tumorigenesis, studies of vertebrate systems have left many questions about the primary targets of Fos in this context unanswered.The functional complexity and redundancy that characterize the mammalian Fos family have motivated a search for simpler and genetically more accessible systems of studying the molecular and biological functions of Fos. In Drosophila melanogaster, D-Fos (als...

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