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1.
J Pers Med ; 14(2)2024 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-38392562

RESUMEN

Sarcomas are a heterogenous group of tumours that commonly carry poor prognosis with limited therapeutic options. Adolescents and young adults (AYAs) with sarcoma are a unique and understudied patient population that have only achieved modest survival gains compared to other groups. We present our institutional experience of AYAs with sarcoma who underwent comprehensive molecular profiling (CMP) via either large-panel targeted DNA sequencing or whole genome and transcriptome sequencing and evaluated the feasibility and clinical impact of this approach. Genomic variants detected were determined to be clinically relevant and actionable following evaluation by the Molecular Tumour Board. Clinicians provided feedback regarding the utility of testing three months after reporting. Twenty-five patients who were recruited for CMP are included in this analysis. The median time from consent to final molecular report was 45 days (interquartile range: 37-57). Potentially actionable variants were detected for 14 patients (56%), and new treatment recommendations were identified for 12 patients (48%). Pathogenic germline variants were identified in three patients (12%), and one patient had a change in diagnosis. The implementation of CMP for AYAs with sarcoma is clinically valuable, feasible, and should be increasingly integrated into routine clinical practice as technologies and turnaround times continue to improve.

2.
Commun Biol ; 7(1): 183, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38360932

RESUMEN

Autophagy, the process of elimination of cellular components by lysosomal degradation, is essential for animal development and homeostasis. Using the autophagy-dependent Drosophila larval midgut degradation model we identified an autophagy regulator, the RING domain ubiquitin ligase CG14435 (detour). Depletion of detour resulted in increased early-stage autophagic vesicles, premature tissue contraction, and overexpression of detour or mammalian homologues, ZNRF1 and ZNRF2, increased autophagic vesicle size. The ablation of ZNRF1 or ZNRF2 in mammalian cells increased basal autophagy. We identified detour interacting proteins including HOPS subunits, deep orange (dor/VPS18), Vacuolar protein sorting 16A (VPS16A), and light (lt/VPS41) and found that detour promotes their ubiquitination. The detour mutant accumulated autophagy-related proteins in young adults, displayed premature ageing, impaired motor function, and activation of innate immunity. Collectively, our findings suggest a role for detour in autophagy, likely through regulation of HOPS complex, with implications for healthy aging.


Asunto(s)
Proteínas de Drosophila , Drosophila , Animales , Drosophila/metabolismo , Transporte de Proteínas , Ubiquitinación , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Autofagia , Mamíferos
3.
Autophagy ; 17(10): 2734-2749, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33112206

RESUMEN

Macroautophagy/autophagy is a highly conserved lysosomal degradative pathway important for maintaining cellular homeostasis. Much of our current knowledge of autophagy is focused on the initiation steps in this process. Recently, an understanding of later steps, particularly lysosomal fusion leading to autolysosome formation and the subsequent role of lysosomal enzymes in degradation and recycling, is becoming evident. Autophagy can function in both cell survival and cell death, however, the mechanisms that distinguish adaptive/survival autophagy from autophagy-dependent cell death remain to be established. Here, using proteomic analysis of Drosophila larval midguts during degradation, we identify a group of proteins with peptidase activity, suggesting a role in autophagy-dependent cell death. We show that Cp1/cathepsin L-deficient larval midgut cells accumulate aberrant autophagic vesicles due to a block in autophagic flux, yet later stages of midgut degradation are not compromised. The accumulation of large aberrant autolysosomes in the absence of Cp1 appears to be the consequence of decreased degradative capacity as they contain undigested cytoplasmic material, rather than a defect in autophagosome-lysosome fusion. Finally, we find that other cathepsins may also contribute to proper autolysosomal degradation in Drosophila larval midgut cells. Our findings provide evidence that cathepsins play an essential role in the autolysosome to maintain basal autophagy flux by balancing autophagosome production and turnover.Abbreviations: 26-29-p: 26-29kD-proteinase; ADCD: autophagy-dependent cell death; Atg8a: Autophagy-related protein 8a; Cp1/cathepsin L: Cysteine proteinase-1; CtsB: Cathepsin B; cathD: cathepsin D; CtsF: Cathepsin F; GFP: green fluorescent protein; LAMP1: lysosomal-associated membrane protein 1; Mitf: microphthalmia associated transcription factor; PCA: principal component analysis; RNAi: RNA interference; RPF: relative to puparium formation.


Asunto(s)
Autofagia , Drosophila , Animales , Autofagia/genética , Catepsina L/metabolismo , Drosophila/genética , Lisosomas/metabolismo , Proteómica
4.
Cell Death Dis ; 10(2): 111, 2019 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-30737370

RESUMEN

The majority of developmentally programmed cell death (PCD) is mediated by caspase-dependent apoptosis; however, additional modalities, including autophagy-dependent cell death, have important spatiotemporally restricted functions. Autophagy involves the engulfment of cytoplasmic components in a double membrane vesicle for delivery to the lysosome. An established model for autophagy-dependent PCD is Drosophila larval midgut removal during metamorphosis. Our previous work demonstrated that growth arrest is required to initiate autophagy-dependent midgut degradation and Target of rapamycin (Tor) limits autophagy induction. In further studies, we uncovered a role for Decapentaplegic (Dpp) in coordinating midgut degradation. Here, we provide new data to show that Dpp interacts with Tor during midgut degradation. Inhibiting Tor rescued the block in midgut degradation due to Dpp signaling. We propose that Dpp is upstream of Tor and down-regulation promotes growth arrest and autophagy-dependent midgut degradation. These findings underscore a relationship between Dpp and Tor signaling in the regulation of cell growth and tissue removal.


Asunto(s)
Proteínas de Drosophila/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Autofagia , Sistema Digestivo/metabolismo , Drosophila , Proteínas de Drosophila/genética , Técnicas de Silenciamiento del Gen , Larva , Transducción de Señal , Serina-Treonina Quinasas TOR/genética
5.
Cell Death Differ ; 26(4): 763-778, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-29959404

RESUMEN

Animal development and homeostasis require the programmed removal of cells. Autophagy-dependent cell deletion is a unique form of cell death often involved in bulk degradation of tissues. In Drosophila the steroid hormone ecdysone controls developmental transitions and triggers the autophagy-dependent removal of the obsolete larval midgut. The production of ecdysone is exquisitely coordinated with signals from numerous organ systems to mediate the correct timing of such developmental programs. Here we report an unexpected role for the Drosophila bone morphogenetic protein/transforming growth factor ß ligand, Decapentaplegic (Dpp), in the regulation of ecdysone-mediated midgut degradation. We show that blocking Dpp signaling induces premature autophagy, rapid cell death, and midgut degradation, whereas sustained Dpp signaling inhibits autophagy induction. Furthermore, Dpp signaling in the midgut prevents the expression of ecdysone responsive genes and impairs ecdysone production in the prothoracic gland. We propose that Dpp has dual roles: one within the midgut to prevent improper tissue degradation, and one in interorgan communication to coordinate ecdysone biosynthesis and developmental timing.


Asunto(s)
Muerte Celular Autofágica , Autofagia/genética , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Ecdisona/metabolismo , Metamorfosis Biológica/genética , Animales , Muerte Celular Autofágica/genética , Autofagia/fisiología , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Drosophila/crecimiento & desarrollo , Proteínas de Drosophila/genética , Regulación del Desarrollo de la Expresión Génica , Larva/citología , Larva/crecimiento & desarrollo , Larva/metabolismo , Lisosomas/genética , Lisosomas/metabolismo , Lisosomas/ultraestructura , Transducción de Señal/genética , Transducción de Señal/fisiología
6.
Int J Dev Biol ; 59(1-3): 23-32, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26374522

RESUMEN

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.


Asunto(s)
Apoptosis/fisiología , Autofagia/fisiología , Drosophila/embriología , Ecdisona/metabolismo , Metamorfosis Biológica/fisiología , Animales , Regulación del Desarrollo de la Expresión Génica , Larva/crecimiento & desarrollo , Pupa/metabolismo
7.
Nat Commun ; 4: 2916, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24336022

RESUMEN

Correct spatial and temporal induction of numerous cell type-specific genes during development requires regulated removal of the repressive histone H3 lysine 27 trimethylation (H3K27me3) modification. Here we show that the H3K27me3 demethylase dUTX is required for hormone-mediated transcriptional regulation of apoptosis and autophagy genes during ecdysone-regulated programmed cell death of Drosophila salivary glands. We demonstrate that dUTX binds to the nuclear hormone receptor complex Ecdysone Receptor/Ultraspiracle, and is recruited to the promoters of key apoptosis and autophagy genes. Salivary gland cell death is delayed in dUTX mutants, with reduced caspase activity and autophagy that coincides with decreased apoptosis and autophagy gene transcripts. We further show that salivary gland degradation requires dUTX catalytic activity. Our findings provide evidence for an unanticipated role for UTX demethylase activity in regulating hormone-dependent cell death and demonstrate how a single transcriptional regulator can modulate a specific complex functional outcome during animal development.


Asunto(s)
Autofagia/genética , Proteínas de Drosophila/metabolismo , Ecdisona/metabolismo , Oxidorreductasas N-Desmetilantes/metabolismo , Glándulas Salivales/citología , Animales , Apoptosis/genética , Caspasas/genética , Caspasas/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Drosophila/citología , Drosophila/genética , Proteínas de Drosophila/genética , Ecdisona/farmacología , Regulación del Desarrollo de la Expresión Génica , Histonas/genética , Histonas/metabolismo , Larva , Metilación , Mutación , Oxidorreductasas N-Desmetilantes/genética , Regiones Promotoras Genéticas , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Glándulas Salivales/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
8.
PLoS One ; 7(10): e47447, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23077619

RESUMEN

BACKGROUND: The spindle assembly checkpoint is crucial for the maintenance of a stable chromosome number. Defects in the checkpoint lead to Chromosomal INstability (CIN), which is linked to the progression of tumors with poor clinical outcomes such as drug resistance and metastasis. As CIN is not found in normal cells, it offers a cancer-specific target for therapy, which may be particularly valuable because CIN is common in advanced tumours that are resistant to conventional therapy. PRINCIPAL FINDINGS: Here we identify genes that are required for the viability of cells with a CIN phenotype. We have used RNAi knockdown of the spindle assembly checkpoint to induce CIN in Drosophila and then screened the set of kinase and phosphatase genes by RNAi knockdown to identify those that induce apoptosis only in the CIN cells. Genes identified include those involved in JNK signaling pathways and mitotic cytoskeletal regulation. CONCLUSIONS/SIGNIFICANCE: The screen demonstrates that it is feasible to selectively kill cells with CIN induced by spindle checkpoint defects. It has identified candidates that are currently being pursued as cancer therapy targets (e.g. Nek2: NIMA related kinase 2), confirming that the screen is able to identify promising drug targets of clinical significance. In addition, several other candidates were identified that have no previous connection with mitosis or apoptosis. Further screening and detailed characterization of the candidates could potentially lead to the therapies that specifically target advanced cancers that exhibit CIN.


Asunto(s)
Apoptosis , Proteínas de Ciclo Celular , Inestabilidad Cromosómica/genética , Puntos de Control de la Fase M del Ciclo Celular/genética , Proteínas Serina-Treonina Quinasas , Animales , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/aislamiento & purificación , Proteínas de Ciclo Celular/metabolismo , Supervivencia Celular/genética , Citoesqueleto/metabolismo , Drosophila/genética , Drosophila/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Sistema de Señalización de MAP Quinasas , Terapia Molecular Dirigida , Quinasa 1 Relacionada con NIMA , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/metabolismo , Fosfotransferasas/genética , Fosfotransferasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/aislamiento & purificación , Proteínas Serina-Treonina Quinasas/metabolismo
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