A Steroid-Triggered Transcriptional Hierarchy Controls Salivary Gland Cell Death during Drosophila Metamorphosis

Jiang, Chenfanfu; Lamblin, Anne Françoise; Steller, Hermann; Thummel, Carl S.

doi:10.1016/s1097-2765(00)80439-6

Cited by 253 publications

(283 citation statements)

References 68 publications

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“…This suppression includes the transcriptional normalization of reaper (Figure 5f), an apoptosis hallmark gene whose transcription is directly regulated by EcR/USP. 35 As expected, dIAP1 transcription is reduced by bsk/JNK↑ and normalized to some extent by EcRB1 W650A (Supplementary Figure S4F). These data favor an apoptosis-type mechanism for the EcR/USPdependent cell death in the PG.…”

Section: After Tool Validation (Supplementary Data and Supplementarysupporting

confidence: 76%

Ligand-independent requirements of steroid receptors EcR and USP for cell survival

2015

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The active form of the Drosophila steroid hormone ecdysone, 20-hydroxyecdysone (20E), binds the heterodimer EcR/USP nuclear receptor to regulate target genes that elicit proliferation, cell death and differentiation during insect development. Although the 20E effects are relatively well known, the physiological relevance of its receptors remains poorly understood. We show here that the prothoracic gland (PG), the major steroid-producing organ of insect larvae, requires EcR and USP to survive in a critical period previous to metamorphosis, and that this requirement is 20E-independent. The cell death induced by the downregulation of these receptors involves the activation of the JNK-encoding basket gene and it can be rescued by upregulating EcR isoforms which are unable to respond to 20E. Also, while PG cell death prevents ecdysone production, blocking hormone synthesis or secretion in normal PG does not lead to cell death, demonstrating further the ecdysone-independent nature of the receptor-deprivation cell death. In contrast to PG cells, wing disc or salivary glands cells do not require these receptors for survival, revealing their cell and developmental time specificity. Exploring the potential use of this feature of steroid receptors in cancer, we assayed tumor overgrowth induced by altered yorkie signaling. This overgrowth is suppressed by EcR downregulation in PG, but not in wing disc, cells. The mechanism of all these cell death features is based on the transcriptional regulation of reaper. These novel and context-dependent functional properties for EcR and USP receptors may help to understand the heterogeneous responses to steroid-based therapies in human pathologies. Steroid hormones control multiple biological processes and, consequently, their faulty regulation underlies many pathologies. 1,2 The main Drosophila steroid hormone, ecdysone, is synthesized in the larval prothoracic gland (PG) using dietary sterols and cytochrome P450 enzymes. 3 Following its pulsated secretion into the hemolymph, peripheral tissues convert ecdysone into biologically active 20-hydroxyecdysone (20E) to control larval molting and metamorphosis. 4 The 20E signal is transduced by heterodimers of two nuclear receptors, ecdysone receptor (EcR) and Ultraspiracle (USP). 5 USP exhibits a single form throughout development. By contrast, EcR encodes three protein isoforms (EcRA, EcRB1 and EcRB2). These show common DNA-and hormone-binding domains but different N-termini although all of them can heterodimerize USP. 6,7 Each EcR isoform is hypothesized to have specific functions based on their distinct spatial and temporal patterns and N-termini. [8][9][10] EcR and USP DNA-binding domains recognize ecdysone response sequences which are short palindromes. 11 Like its vertebrate counterparts, 12 the ligand-EcR/USP complex activates transcription, whereas the unliganded receptor act as a repressor. [13][14][15] The in vivo validation of repressor activities for unliganded complexes, however, is mostly indirect. For example, EcR or USP loss...

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Section: After Tool Validation (Supplementary Data and Supplementarysupporting

confidence: 76%

Ligand-independent requirements of steroid receptors EcR and USP for cell survival

2015

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“…21,22 Although these results could be interpreted to indicate that IAPs do not play a major role for caspase regulation in mammals, a more likely alternative is that their physiological role is masked by functional redundancy. If relatively short-lived organisms such as fruit flies protect themselves against unwanted death using multiple caspase inhibitors (see below; Figure 1), 6,[8][9][10][11][12][13][14][15][23][24][25][26][27][28][29][30][31][32][33][34][35] it would come as a great surprise if mammals would employ fewer safeguards to control caspase activity.…”

Section: Brakes On Death: Caspase Inhibition By Inhibitor Of Apoptosimentioning

confidence: 99%

“…38 The reaper gene, and to some extent grim, hid and sickle, are transcriptionally activated in response to many different proapoptotic signals, including steroid hormones, a variety of developmental signals, radiation and various forms of cellular stress or injury. [24][25][26]36,[39][40][41] These genes share a very large, complex regulatory region containing numerous enhancer (and silencer) elements that are the target for many different transcriptional regulators. Therefore, one major mechanism by which different signaling pathways converge in Drosophila is through transcriptional activation of reaper, hid and grim.…”

Section: Relieving the Brakes: Induction Of Apoptosis By Reaper-familmentioning

confidence: 99%

Regulation of apoptosis in Drosophila

2008

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Insects have made major contributions to understanding the regulation of cell death, dating back to the pioneering work of Lockshin and Williams on death of muscle cells during postembryonic development of Manduca. A physically smaller cousin of moths, the fruit fly Drosophila melanogaster, offers unique advantages for studying the regulation of cell death in response to different apoptotic stimuli in situ. Different signaling pathways converge in Drosophila to activate a common death program through transcriptional activation of reaper, hid and grim. Reaper-family proteins induce apoptosis by binding to and antagonizing inhibitor of apoptosis proteins (IAPs), which in turn inhibit caspases. This switch from life to death relies extensively on targeted degradation of cell death proteins by the ubiquitin-proteasome pathway. Drosophila IAP-1 (Diap1) functions as an E3-ubiquitin ligase to protect cells from unwanted death by promoting the degradation of the initiator caspase Dronc. However, in response to apoptotic signals, Reaper-family proteins are produced, which promote the auto-ubiquitination and degradation of Diap1, thereby removing the 'brakes on death' in cells that are doomed to die. More recently, several other ubiquitin pathway proteins were found to play important roles for caspase regulation, indicating that the control of cell survival and death relies extensively on targeted degradation by the ubiquitin-proteasome pathway.

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“…On studying leg morphogenesis, we have observed that a reporter construct that reproduces the expression of the pro-apoptotic gene reaper (rpr) 5 shows a restricted segmental expression pattern in the third instar and prepupal leg disc: it is expressed in concentric rings, 2 to 6 cells wide, precisely located at the presumptive joint in the distal part of the leg, from the tibia to the fifth tarsal segment (Fig. 1A, B, I, J).…”

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confidence: 99%

Sharp boundaries of Dpp signalling trigger local cell death required for Drosophila leg morphogenesis

2006

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Telephone number: (33) 4 92 07 64 62. Keywords : dpp, apoptosis, Drosophila, leg morphogenesis, rpr, JNK signaling.Con formato: Español (España -alfab. internacional) Eliminado:2 Morphogens are secreted signaling molecules that govern many developmental processes 1 . In the Drosophila wing disc, the TGFβ homolog Decapentaplegic (Dpp) morphogen forms a smooth gradient and specifies cell fate by conferring a defined value of morphogen activity. Thus, neighboring cells have similar amounts of Dpp product, and if a sharp discontinuity in Dpp activity is generated between them, JNK-dependent apoptosis is triggered to restore graded positional information 2,3 . So far, it has been implicitly assumed that this apoptotic process is only activated when normal signaling is distorted. We have found, however, that a similar process occurs during normal development. We demonstrate here that a rupture in Dpp activity takes place during normal segmentation of the distal legs of Drosophila. This sharp boundary of Dpp signaling, independently of the absolute level of Dpp activity, induces a JNK/reaper-dependent apoptosis required for the morphogenesis of a particular structure of the leg, the joint. Hence, our results show that Dpp could induce a developmental program not only in a concentration dependent manner, but also by the creation of a sharp boundary of Dpp activity. Furthermore, they show that the same process could be used either to restore a normal pattern in response to artificial disturbance or to direct a morphogenetic process.The Drosophila leg is an appendage composed of nine segments: coxa, trochanter, femur, tibia and five tarsal segments (T1 to T5), separated by flexible structures named joints. The leg develops from the leg imaginal disc, a group of cells which segregates at the end of embryogenesis, proliferates during the larval stages and evaginates during pupation to form the adult appendages. During the third instar larval stage, a progressive subdivision of the future leg occurs 4 . This is reflected in the successive formation of folds in the disc, which prefigures the location of each future joint. Hence, cells located in the folds could be considered as the presumptive joint.On studying leg morphogenesis, we have observed that a reporter construct that reproduces the expression of the pro-apoptotic gene reaper (rpr) 5 shows a restricted segmental expression pattern in the third instar and prepupal leg disc: it is expressed in concentric rings, 2 to 6 cells wide, precisely located at the presumptive joint in the distal part of the leg, from the tibia to the fifth tarsal segment (Fig. 1A, B, I, J). rpr is a potent activator of caspases 6 , a unique family of cysteine proteases that execute programmed cell death. Caspases are produced as zymogens and have to be activated at the onset of apoptosis to degrade cellular substrates, thus causing cell death. To see if the expression of rpr indicates that apoptotic cells are present in the presumptive joint, we stained third instar and prepupal leg discs with a...

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A Steroid-Triggered Transcriptional Hierarchy Controls Salivary Gland Cell Death during Drosophila Metamorphosis

Cited by 253 publications

References 68 publications

Ligand-independent requirements of steroid receptors EcR and USP for cell survival

Ligand-independent requirements of steroid receptors EcR and USP for cell survival

Regulation of apoptosis in Drosophila

Sharp boundaries of Dpp signalling trigger local cell death required for Drosophila leg morphogenesis

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