A molecular link A molecular link between Hairless and Pros26.4, a member of the AAA-ATPase subunits of the proteasome 19S regulatory particle in<i>Drosophila</i>

Müller, Dominik; Nagel, Anja C.; Maier, Dieter; Preiss, Anette

doi:10.1242/jcs.02743

Cited by 13 publications

(29 citation statements)

References 45 publications

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“…The physiological importance of proteasome integrity during Drosophila eye development is further supported by a previous study in which depletion of Pros26.4 (encodes the Rpn2 orthologue in Drosophila ) within the differentiating eye field resulted in fused ommatidia and a graded loss of internal retinal tissue, while a strong increase in cell death was also observed in the third instar larval eye discs [35]. E3 ubiquitin ligases have been also shown to control both the differentiating signal and the proliferation regulation of Drosophila eye development, through distinct F-box proteins (Slimb and Ago, respectively) [36].…”

Section: Discussionmentioning

confidence: 52%

Proteasome, but Not Autophagy, Disruption Results in Severe Eye and Wing Dysmorphia: A Subunit- and Regulator-Dependent Process in Drosophila

Velentzas

Pantazi

et al. 2013

PLoS ONE

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Proteasome-dependent and autophagy-mediated degradation of eukaryotic cellular proteins represent the two major proteostatic mechanisms that are critically implicated in a number of signaling pathways and cellular processes. Deregulation of functions engaged in protein elimination frequently leads to development of morbid states and diseases. In this context, and through the utilization of GAL4/UAS genetic tool, we herein examined the in vivo contribution of proteasome and autophagy systems in Drosophila eye and wing morphogenesis. By exploiting the ability of GAL4-ninaE. GMR and P{GawB}BxMS1096 genetic drivers to be strongly and preferentially expressed in the eye and wing discs, respectively, we proved that proteasomal integrity and ubiquitination proficiency essentially control fly’s eye and wing development. Indeed, subunit- and regulator-specific patterns of severe organ dysmorphia were obtained after the RNAi-induced downregulation of critical proteasome components (Rpn1, Rpn2, α5, β5 and β6) or distinct protein-ubiquitin conjugators (UbcD6, but not UbcD1 and UbcD4). Proteasome deficient eyes presented with either rough phenotypes or strongly dysmorphic shapes, while transgenic mutant wings were severely folded and carried blistered structures together with loss of vein differentiation. Moreover, transgenic fly eyes overexpressing the UBP2-yeast deubiquitinase enzyme were characterized by an eyeless-like phenotype. Therefore, the proteasome/ubiquitin proteolytic activities are undoubtedly required for the normal course of eye and wing development. In contrast, the RNAi-mediated downregulation of critical Atg (1, 4, 7, 9 and 18) autophagic proteins revealed their non-essential, or redundant, functional roles in Drosophila eye and wing formation under physiological growth conditions, since their reduced expression levels could only marginally disturb wing’s, but not eye’s, morphogenetic organization and architecture. However, Atg9 proved indispensable for the maintenance of structural integrity of adult wings in aged flies. In toto, our findings clearly demonstrate the gene-specific fundamental contribution of proteasome, but not autophagy, in invertebrate eye and wing organ development.

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Section: Discussionmentioning

confidence: 52%

Proteasome, but Not Autophagy, Disruption Results in Severe Eye and Wing Dysmorphia: A Subunit- and Regulator-Dependent Process in Drosophila

Velentzas

Pantazi

et al. 2013

PLoS ONE

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“…Finally, if ectopic Notch signaling downstream of loss of Abl is a primary driver of photoreceptor dedifferentiation, then upregulating Notch signaling directly in the pupal photoreceptor cells might be sufficient to induce loss of neuronal marker expression. To minimize the gross disruptions to retinal morphology associated with GMR-Gal4 driven expression of the NICD (Müller et al, 2006), a constitutively active allele of Notch, we employed the temperature-sensitive TARGET gene expression system (McGuire et al, 2004). Thus at 18°C, the permissive condition for the temperature-sensitive allele of the Gal4 repressor protein Gal80, UAS-NICD expression was not induced, and regular lattices of Elav + cells were observed in adult eyes (Fig.…”

Section: Increased Notch Signaling Contributes To Loss Of Neuronal Famentioning

confidence: 99%

The Abelson tyrosine kinase regulates Notch endocytosis and signaling to maintain neuronal cell fate inDrosophilaphotoreceptors

2013

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SUMMARYThe development of a functional organ requires coordinated programs of cell fate specification, terminal differentiation and morphogenesis. Whereas signaling mechanisms that specify individual cell fates are well documented, little is known about the pathways and molecules that maintain these fates stably as normal development proceeds or how their dysregulation may contribute to altered cell states in diseases such as cancer. In Drosophila, the tyrosine kinase Abelson (Abl) interfaces with multiple signaling pathways to direct epithelial and neuronal morphogenesis during embryonic and retinal development. Here we show that Abl is required for photoreceptor cell fate maintenance, as Abl mutant photoreceptors lose neuronal markers during late pupal stages but do not re-enter a proliferative state or undergo apoptosis. Failure to maintain the differentiated state correlates with impaired trafficking of the Notch receptor and ectopic Notch signaling, and can be suppressed by reducing the genetic dose of Notch or of its downstream transcriptional effector Suppressor of Hairless. Together, these data reveal a novel mechanism for maintaining the terminally differentiated state of Drosophila photoreceptors and suggest that neuronal fates in the fly retina retain plasticity late into development. Given the general evolutionary conservation of developmental signaling mechanisms, Abl-mediated regulation of Notch could be broadly relevant to cell fate maintenance and reprogramming during normal development, regeneration and oncogenic transformation.

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“…At the onset of apoptosis, Diap1 undergoes post-transcriptional modifications, leading to a proteasome-mediated degradation of the Diap1 protein (for a review, see Palaga and Osborne, 2002). Given the fact that H directly interacts with a component of the regulatory cap of the proteasome (Müller et al, 2006), we reasoned that H might be involved in targeting Diap1 for degradation. However, we could not detect any direct physical binding between H and Diap1 in yeast two-hybrid assays and in co-immunoprecipitation experiments, indicating that H and Diap1 are not in the same protein complexes in the tissues analysed (data not shown).…”

Section: H-mediated Cell Death Does Not Involve Diap1 E2f or Eyegonementioning

confidence: 99%

“…Yeast two-hybrid protein interaction assays were performed as described (Müller et al, 2006) using pEG-HFL and pJG-DIAP1. The latter was generated by cloning the coding region of diap1 in frame into the EcoRI/XhoI sites of pJG.…”

Section: Protein Interaction Studies and Immunohistochemistrymentioning

confidence: 99%

“…Alternatively, aos and klu levels might be increased as a consequence of the downregulation, by H, of an as yet unknown repressor. Since H behaves as a kind of 'multi-adaptor protein', which not only recruits the transcriptional silencers Gro and CtBP to Notch targets but also binds other proteins such as Pros26.4 (Müller et al, 2006), it is also possible that H interacts with positive regulators of lz, klu and aos.…”

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confidence: 99%

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Hairless induces cell death by downregulation of EGFR signalling activity

Protzer

Wech

Nagel

2008

Journal of Cell Science

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Overexpression of the Notch antagonist Hairless (H) during imaginal development in Drosophila is correlated with tissue loss and cell death. Together with the co-repressors Groucho (Gro) and C-terminal binding protein (CtBP), H assembles a repression complex on Notch target genes, thereby downregulating Notch signalling activity. Here we investigated the mechanisms underlying H-mediated cell death in S2 cell culture and in vivo during imaginal development in Drosophila. First, we mapped the domains within the H protein that are required for apoptosis induction in cell culture. These include the binding sites for the co-repressors, both of which are essential for H-mediated cell death during fly development. Hence, the underlying cause of H-mediated apoptosis seems to be a transcriptional downregulation of Notch target genes involved in cell survival. In a search for potential targets, we observed transcriptional downregulation of rho-lacZ and EGFR signalling output. Moreover, the EGFR antagonists lozenge, klumpfuss and argos were all activated upon H overexpression. This result conforms to the proapoptotic activity of H, as these factors are known to be involved in apoptosis induction. Together, the results indicate that H induces apoptosis by downregulation of EGFR signalling activity. This highlights the importance of a coordinated interplay of Notch and EGFR signalling pathways for cell survival during Drosophila development.

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A molecular link A molecular link between Hairless and Pros26.4, a member of the AAA-ATPase subunits of the proteasome 19S regulatory particle inDrosophila

Cited by 13 publications

References 45 publications

Proteasome, but Not Autophagy, Disruption Results in Severe Eye and Wing Dysmorphia: A Subunit- and Regulator-Dependent Process in Drosophila

Proteasome, but Not Autophagy, Disruption Results in Severe Eye and Wing Dysmorphia: A Subunit- and Regulator-Dependent Process in Drosophila

The Abelson tyrosine kinase regulates Notch endocytosis and signaling to maintain neuronal cell fate inDrosophilaphotoreceptors

Hairless induces cell death by downregulation of EGFR signalling activity

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