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Drosophila cancer

Jewel L Podratz, Han Lee, Patrizia Knorr, Stephanie Koehler, Steven Forsythe, Kelsey Lambrecht, Suzette Arias, Kiley Schmidt, Gabrielle Steinhoff, Georgiy Yudintsev, Amy Yang, Eugenia Trushina, Anthony Windebank
Cisplatin is an effective chemotherapy drug that induces peripheral neuropathy in cancer patients. In rodent dorsal root ganglion neurons, cisplatin binds nuclear and mitochondrial DNA (mtDNA) inducing DNA damage and apoptosis. Platinum-mtDNA adducts inhibit mtDNA replication and transcription leading to mitochondrial degradation. Cisplatin also induces climbing deficiencies associated with neuronal apoptosis in adult Drosophila melanogaster. Here we used Drosophila larvae that express green fluorescent protein in the mitochondria of motor neurons to observe the effects of cisplatin on mitochondrial dynamics and function...
October 17, 2016: Neurobiology of Disease
Orkun Akin, S Lawrence Zipursky
Axon guidance is proposed to act through a combination of long- and short-range attractive and repulsive cues. The ligand-receptor pair, Netrin (Net) and Frazzled (Fra) (DCC, Deleted in Colorectal Cancer, in vertebrates), is recognized as the prototypical effector of chemoattraction, with roles in both long- and short-range guidance. In the Drosophila visual system, R8 photoreceptor growth cones were shown to require Net-Fra to reach their target, the peak of a Net gradient. Using live imaging, we show, however, that R8 growth cones reach and recognize their target without Net, Fra, or Trim9, a conserved binding partner of Fra, but do not remain attached to it...
October 15, 2016: ELife
Xing Ma, Yingying Han, Xiaoqing Song, Trieu Do, Zhihao Yang, Jianquan Ni, Ting Xie
Stem cells in adult tissues are constantly exposed to genotoxic stress and also accumulate DNA damage with age. DNA damage has been proposed to cause stem cell loss and cancer formation. However, it remains a mystery how DNA damage leads to both stem cell loss and cancer formation. In this study, we use germline stem cells (GSCs) in the Drosophila ovary to show that DNA damage retards stem cell self-renewal and lineage differentiation in a CHK2 kinase-dependent manner. Both heatshock-inducible endonuclease I-CreI expression and X-ray irradiation can efficiently introduce double-strand breaks in GSCs and their progeny, resulting in a rapid GSC loss and an accumulation of ill-differentiated GSC progeny...
October 11, 2016: Development
Satoru Wakabayashi, Naoya Sawamura, André Voelzmann, Meike Broemer, Toru Asahi, Michael Hoch
Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that is highly conserved in animals and plants. CRBN proteins have been implicated in various biological processes such as development, metabolism, learning and memory formation and their impairment has been linked to autosomal recessive non-syndromic intellectual disability and cancer. Furthermore, human CRBN was identified as the primary target of thalidomide teratogenicity. Data on functional analysis of CRBN family members in vivo is, however, still scarce...
October 4, 2016: Journal of Biological Chemistry
Weiyue Zheng, Masataka Umitsu, Ishaan Jagan, Charles W Tran, Noboru Ishiyama, Michael BeGora, Kiyomi Araki, Pamela S Ohashi, Mitsuhiko Ikura, Senthil K Muthuswamy
The polarity protein Scribble (SCRIB) regulates apical-basal polarity, directional migration and tumour suppression in Drosophila and mammals. Here we report that SCRIB is an important regulator of myeloid cell functions including bacterial infection and inflammation. SCRIB interacts directly with the NADPH oxidase (NOX) complex in a PSD95/Dlg/ZO-1 (PDZ)-domain-dependent manner and is required for NOX-induced reactive oxygen species (ROS) generation in culture and in vivo. On bacterial infection, SCRIB localized to phagosomes in a leucine-rich repeat-dependent manner and promoted ROS production within phagosomes to kill bacteria...
October 3, 2016: Nature Cell Biology
Delia Ricolo, Myrto Deligiannaki, Jordi Casanova, Sofia J Araújo
Centrosome amplification is a hallmark of cancer, although we are still far from understanding how this process affects tumorigenesis [1, 2]. Besides the contribution of supernumerary centrosomes to mitotic defects, their biological effects in the post-mitotic cell are not well known. Here, we exploit the effects of centrosome amplification in post-mitotic cells during single-cell branching. We show that Drosophila tracheal cells with extra centrosomes branch more than wild-type cells. We found that mutations in Rca1 and CycA affect subcellular branching, causing tracheal tip cells to form more than one subcellular lumen...
September 17, 2016: Current Biology: CB
Sung-Tae Hong, Kwang-Wook Choi
Genome stability is essential for all organisms. Translationally controlled tumour protein (TCTP) is a conserved protein associated with cancers. TCTP is involved in multiple intracellular functions, but its role in transcription and genome stability is poorly understood. Here, we demonstrate new functions of Drosophila TCTP (Tctp) in transcription and the stability of repeated sequences (rDNA and pericentromeric heterochromatin). Tctp binds Brahma (Brm) chromatin remodeler to negatively modulate its activity...
2016: Nature Communications
Shree Ram Singh, Xiankun Zeng, Jiangsha Zhao, Ying Liu, Gerald Hou, Hanhan Liu, Steven X Hou
Cancer stem cells (CSCs) may be responsible for tumour dormancy, relapse and the eventual death of most cancer patients. In addition, these cells are usually resistant to cytotoxic conditions. However, very little is known about the biology behind this resistance to therapeutics. Here we investigated stem-cell death in the digestive system of adult Drosophila melanogaster. We found that knockdown of the coat protein complex I (COPI)-Arf79F (also known as Arf1) complex selectively killed normal and transformed stem cells through necrosis, by attenuating the lipolysis pathway, but spared differentiated cells...
September 28, 2016: Nature
Youheng Wei, Brad Reveal, Weili Cai, Mary A Lilly
TORC1 regulates metabolism and growth in response to a large array of upstream inputs. The evolutionary conserved trimeric GATOR1 complex inhibits TORC1 activity in response to amino acid limitation. In humans, the GATOR1 complex has been implicated in a wide array of pathologies including cancer and hereditary forms of epilepsy. However, the precise role of GATOR1 in animal physiology remains largely undefined. Here we characterize null mutants of the GATOR1 components nprl2, nprl3 and iml1 in Drosophila melanogaster We demonstrate that all three mutants have inappropriately high baseline levels of TORC1 activity and decreased adult viability...
September 26, 2016: G3: Genes—Genomes—Genetics
Benjamin P Towler, Christopher I Jones, Kirsty L Harper, Joseph A Waldron, Sarah F Newbury
In a complex organism, cell proliferation and apoptosis need to be precisely controlled in order for tissues to develop correctly. Excessive cell proliferation can lead to diseases such as cancer. We have shown that the exoribonuclease Dis3L2 is required for the correct regulation of proliferation in a natural tissue within the model organism Drosophila melanogaster. Dis3L2 is a member of a highly conserved family of exoribonucleases that degrade RNA in a 3'-5' direction. We show that knockdown of dis3L2 in the Drosophila wing imaginal discs results in substantial wing overgrowth due to increased cellular proliferation rather than an increase in cell size...
September 14, 2016: RNA Biology
Srijit Das, Seong Lin Teoh
The incidence of lung cancers has increased globally. Increased exposure to tobacco, passive smoking, less consumption of vegetables and fruits and occupational exposure to asbestos, arsenic and chromium are the main risk factors. The pathophysiology of lung cancer is complex and not well understood. Various microRNAs, genes and pathways are associated with lung cancers. The genes involved in lung cancers produce proteins involved in cell growth, differentiation, different cell cycles, apoptosis, immune modulation, tumor spread and progression...
September 7, 2016: Current Drug Targets
Sarah Levinson, Ross L Cagan
We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities...
September 13, 2016: Cell Reports
Qanber Raza, J Roger Jacobs
Collective cell migration is the coordinated movement of cells, which organize tissues during morphogenesis, repair and some cancers. The motile cell membrane of the advancing front in collective cell migration is termed the Leading Edge. The embryonic development of the vertebrate and Drosophila hearts are both characterized by the coordinated medial migration of a bilateral cluster of mesodermal cells. In Drosophila, the cardioblasts form cohesive bilateral rows that migrate collectively as a unit towards the dorsal midline to form the dorsal vessel...
September 9, 2016: Developmental Biology
Patrick Verrando, Maria Capovilla, Roger Rahmani
Epidemiological association studies have revealed a role for pesticides in cancer occurrence, while a growing number of reports have highlighted the deleterious epigenetic modifications that can be produced by environmental factors. However, epidemiological data currently lack molecular support to unravel the epigenetic impact of pesticides on carcinogenesis. Based on epidemiological studies of melanoma, our data show for the first time that trans-nonachlor (TNC), a component of the pesticide chlordane, modulates the microRNA miR-141-3p in human melanocytic cells in vitro, with effects on melanomagenesis parameters...
August 10, 2016: Toxicology
Susumu Hirabayashi
Accumulating epidemiological evidence indicates a strong clinical association between obesity and an increased risk of cancer. The global pandemic of obesity indicates a public health trend towards a substantial increase in cancer incidence and mortality. However, the mechanisms that link obesity to cancer remain incompletely understood. The fruit fly Drosophila melanogaster has been increasingly used to model an expanding spectrum of human diseases. Fly models provide a genetically simpler system that is ideal for use as a first step towards dissecting disease interactions...
September 1, 2016: Disease Models & Mechanisms
Dawei Liu, Zeeshan Shaukat, Tianqi Xu, Donna Denton, Robert Saint, Stephen Gregory
Chromosomal instability (CIN) refers to genomic instability in which cells have gained or lost chromosomes or chromosomal fragments. A high level of CIN is common in solid tumours and is associated with cancer drug resistance and poor prognosis. The impact of CIN-induced stress and the resulting cellular responses are only just beginning to emerge. Using proliferating tissue in Drosophila as a model, we found that autophagy is activated in CIN cells and is necessary for their survival. Specifically, increasing the removal of defective mitochondria by mitophagy is able to lower levels of reactive oxygen species and the resultant cellular damage that is normally seen in CIN cells...
August 31, 2016: Oncotarget
Cheng-Wei Wang, Arunima Purkayastha, Kevin T Jones, Shivani K Thaker, Utpal Banerjee
A well-characterized metabolic landmark for aggressive cancers is the reprogramming from oxidative phosphorylation to aerobic glycolysis, referred to as the Warburg effect. Models mimicking this process are often incomplete due to genetic complexities of tumors and cell lines containing unmapped collaborating mutations. In order to establish a system where individual components of oncogenic signals and metabolic pathways can be readily elucidated, we induced a glycolytic tumor in the Drosophila wing imaginal disc by activating the oncogene PDGF/VEGF-receptor (Pvr)...
2016: ELife
Tetsuhisa Otani, Yosuke Ogura, Kazuyo Misaki, Takuya Maeda, Akiyo Kimpara, Shigenobu Yonemura, Shigeo Hayashi
Signaling molecules have pleiotropic functions and are activated by various extracellular stimuli. Protein kinase C (PKC) is activated by diverse receptors, and its dysregulation is associated with diseases including cancer. However, how the undesired activation of PKC is prevented during development remains poorly understood. We have previously shown that a protein kinase, IKKϵ, is active at the growing bristle tip and regulates actin bundle organization during Drosophila bristle morphogenesis. Here we demonstrate that IKKϵ regulates the actin bundle localization of a dynamic actin cross-linker, Fascin...
August 30, 2016: Development
Lin Ding, Mohamad El Zaatari, Juanita L Merchant
This review focuses on the various experimental models to study gastric cancer pathogenesis, with the role of genetically engineered mouse models (GEMMs) used as the major examples. We review differences in human stomach anatomy compared to the stomachs of the experimental models, including the mouse and invertebrate models such as Drosophila and C. elegans. The contribution of major signaling pathways, e.g., Notch, Hedgehog, AKT/PI3K is discussed in the context of their potential contribution to foregut tumorigenesis...
2016: Advances in Experimental Medicine and Biology
L J Kay, T K Smulders-Srinivasan, M Soundararajan
The dual-specificity tyrosine (Y) phosphorylation-regulated kinase DYRK1A, also known as Down syndrome (DS) kinase, is a dosage-dependent signaling kinase that was originally shown to be highly expressed in DS patients as a consequence of trisomy 21. Although this was evident some time ago, it is only in recent investigations that the molecular roles of DYRK1A in a wide range of cellular processes are becoming increasingly apparent. Since initial knowledge on DYRK1A became evident through minibrain mnb, the Drosophila homolog of DYRK1A, this review will first summarize the scientific reports on minibrain and further expand on the well-established neuronal functions of mammalian and human DYRK1A...
2016: Advances in Protein Chemistry and Structural Biology
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