EcR isoforms in<i>Drosophila</i>: testing tissue-specific requirements by targeted blockade and rescue

Cherbas, Lucy; Hu, Xiao; Жимулев, И. Ф.; Belyaeva, E. S.; Cherbas, Peter

doi:10.1242/dev.00205

Cited by 314 publications

(320 citation statements)

References 88 publications

(73 reference statements)

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“…To investigate how BM remodeling contributes to tissue development, we chose to inhibit MMP function by targeted overexpression of the Drosophila tissue inhibitor of metalloproteases (TIMP) (14) using the UAS/GAL4 system (15). Overexpression of TIMP in the larval fat body, driven by Lsp2-GAL4 (Lsp2ϾTIMP) (16) and in the peripodial epithelium of the larval wing imaginal discs, by Ubx-GAL4 (UbxϾTIMP) (17), resulted in striking phenotypes that we focused on for further characterization [ Fig. 1 and supporting information (SI) Fig.…”

Section: Reduction Of Mmp Activities Results In Disc Eversionmentioning

confidence: 99%

Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion

Srivastava

Pastor-Pareja

Igaki

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

186

245

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Organ and tissue integrity is often maintained in animals by a specialized extracellular matrix structure called the basement membrane (BM). Accumulated evidence indicates that BM remodeling occurs during development and tumor invasion. Although the BM organizes and functions at the organ level, most past studies have explored its biochemical and in vitro properties. In this study, we monitor the BM in vivo during developmental tissue invasion for disc eversion and tumor invasion in Drosophila and modulate BM integrity with genetic alterations affecting either the whole organism or the targeted discs or tumors. We observe that the degradation of BM by the discs or the tumors is an early event during invasion processes and that preventing BM degradation completely blocks both tissue and tumor invasion, indicating that modulation of BM is essential for developmental and tumor invasion. Furthermore, elements of the invasion machinery, including JNK-induced matrix metalloproteinase (MMP) expression, are shared by both disc eversion and tumor invasion processes. Moreover, we show that although expression of MMP inhibitor, TIMP, is sufficient to halt developmental invasion, inhibition of proteases by both TIMP and RECK are required to block tumor invasion. These data suggest that tumor cells have a more robust invasion mechanism and could acquire metastatic behavior by co-opting developmental invasion programs. This type of co-option may be a general feature contributing to the progression of tumors. Finally, although past efforts using MMP inhibitors have not yielded much success, our results strongly argue that BM modulation could be a critical target for cancer therapy.developmental invasion ͉ JNK signaling ͉ tumor metastasis ͉ matrix metalloproteinase

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Section: Reduction Of Mmp Activities Results In Disc Eversionmentioning

confidence: 99%

Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion

Srivastava

Pastor-Pareja

Igaki

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

186

245

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“…E74 encodes two transcription factor isoforms of the ets proto-oncogene family, both with proven functions in larval muscles during pupariation and pupation. A recent report also shows a global block to development can occur with the forced expression of dominant-negative versions of the ecdysone receptor, even when this expression is restricted locally to specific cell or tissue types (24). The generation of comparable phenotypes by mcanA act expression may be indicative of a role for the phosphatase in the normal reprogramming of gene expression during early metamorphosis.…”

Section: Discussionmentioning

confidence: 99%

Requirement of the calcineurin subunit gene canB2 for indirect flight muscle formation in Drosophila

Gajewski

Wang

Molkentin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Calcineurin is a calcium-activated protein phosphatase involved in multiple aspects of cardiac and skeletal muscle development and disease. Genes encoding calcineurin subunit proteins are highly conserved among animal species. Toward the goal of identifying new calcineurin-interacting loci that function in myogenic processes, we expressed an activated form of mouse calcineurin A in Drosophila and screened for suppressors of the phosphataseinduced lethality. Here, we demonstrate that a mutation in the canB2 gene, which encodes a regulatory subunit of Drosophila calcineurin, can suppress a pupal developmental arrest phenotype to adult viability. As canB2 is an essential gene and rare homozygous escapers are flightless, we further analyzed canB2 expression and function in pupae and adults. The gene is expressed in the forming indirect flight muscles and central nervous system during pupal development. A canA gene is comparably expressed in these tissues. Consistent with the observed muscle expression, canB2 mutants exhibit severe defects in the organization of their indirect flight muscles, a phenotype that is likely caused by muscle hypercontractility. Together, these findings demonstrate a vital role for the phosphatase in this specific facet of Drosophila myogenesis and show conserved fly and vertebrate calcineurin genes contribute prominently to fundamental processes of muscle formation and function.

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“…7,15 The observation that EcR↑ rescues USP↓, suggests that the normal repression by EcR/ USP heterodimers can be efficiently carried out by EcR alone, either acting as a monomer or as a homodimer. Alternatively, in the absence of USP, EcR could heterodimerize with a third, unknown, receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, mutated EcR isoforms that do not bind ecdysone, EcRB1 W650A , or cannot activate target gene transcription, EcRB1 F645A , 7 rescue to some extent the metamorphosis blockade ( Figure 4b). This is additional evidence that EcR/USP-dependent effects in the PG are ecdysone-independent.…”

Section: After Tool Validation (Supplementary Data and Supplementarymentioning

confidence: 99%

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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EcR isoforms inDrosophila: testing tissue-specific requirements by targeted blockade and rescue

Cited by 314 publications

References 88 publications

Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion

Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion

Requirement of the calcineurin subunit gene canB2 for indirect flight muscle formation in Drosophila

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

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