A steroid-controlled global switch in sensitivity to apoptosis during Drosophila development

Kang, Yunsik; Bashirullah, Arash

doi:10.1016/j.ydbio.2013.12.005

Cited by 24 publications

(29 citation statements)

References 62 publications

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“…Recently, evidences have been gathered indicating that sensitivity to apoptosis is acquired by tissues at two specific steps during development, embryogenesis and pupariation. 39 The data on EcR and USP coincide with the pupariation time requirement and provide a mechanism for this sensitivity.…”

Section: Discussionmentioning

confidence: 77%

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: Discussionmentioning

confidence: 77%

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

2015

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“…During the middle of the third instar larval stage, low-titre pulses of ecdysone trigger a switch in the mechanism of caspase activation from apoptosome-independent to apoptosome-dependent through upregulation of the apoptosome components dark and dronc as well as drice (Kang and Bashirullah, 2014). Towards the end of the third instar larval stage a high-titre pulse of ecdysone initiates larval-pupal metamorphosis and destruction of the larval midgut, and abdominal and anterior muscles (Cakouros et al, 2004b, Fahrbach et al, 2005, Jiang et al, 1997, Lee et al, 2002a, Yin and Thummel, 2005, Zirin et al, 2013.…”

Section: Ecdysone-regulated Pcdmentioning

confidence: 99%

Ecdysone-mediated programmed cell death in Drosophila

Nicolson

Denton²,

Kumar³

2015

Int. J. Dev. Biol.

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During Drosophila development, the steroid hormone ecdysone plays a key role in the transition from embryo into larva and then into pupa. It is during larval-pupal metamorphosis that extensive programmed cell death occurs to remove large obsolete larval tissues. During this transition, ecdysone pulses control the expression of specific transcription factors which drive the expression of key genes involved in cell death, thus spatially and temporally controlling programmed cell death. Ecdysone also controls cell death in specific larval and adult tissues. This review focuses on the current knowledge of ecdysone-mediated cell death in Drosophila.

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“…15 Whereas the mechanisms responsible for these differences in the intensity and dynamics of caspase-3 activation are not clear, they were at least in part attributed to low levels of activation and duration of the proapoptotic BCL-2 family members Bad and Bax. 16 Other modes of caspase regulation in CDPs may include tight control over the transcriptional and/or translational levels of caspases and upstream pro-apoptotic regulatory genes, 17,18 post-translational modifications of pro-and anti-apoptotic proteins, 19 and spatiotemporal or level modulation of antiapoptotic genes. 13,20 Finally, effector caspase-independent, non-catalytic (yet unknown) function of the Drosophila initiator caspase-9 ortholog, Dronc, has been recently proposed to induce compensatory proliferation, 21 implying that some CDPs may avoid the lethal activity of the effector caspases altogether.…”

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confidence: 99%