Publications by authors named "Tom V Lee"

18 Publications

  • Page 1 of 1

Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models.

Cell Rep 2020 07;32(2):107908

Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.

We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.
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http://dx.doi.org/10.1016/j.celrep.2020.107908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428328PMC
July 2020

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019

A Portal to Visualize Transcriptome Profiles in Mouse Models of Neurological Disorders.

Genes (Basel) 2019 09 26;10(10). Epub 2019 Sep 26.

Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

Target nomination for drug development has been a major challenge in the path to finding a cure for several neurological disorders. Comprehensive transcriptome profiles have revealed brain gene expression changes associated with many neurological disorders, and the functional validation of these changes is a critical next step. Model organisms are a proven approach for the elucidation of disease mechanisms, including screening of gene candidates as therapeutic targets. Frequently, multiple models exist for a given disease, creating a challenge to select the optimal model for validation and functional follow-up. To help in nominating the best mouse models for studying neurological diseases, we developed a web portal to visualize mouse transcriptomic data related to neurological disorders: http://mmad.nrihub.org. Users can examine gene expression changes across mouse model studies to help select the optimal mouse model for further investigation. The portal provides access to mouse studies related to Alzheimer's diseases (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), Spinocerebellar ataxia (SCA), and models related to aging.
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http://dx.doi.org/10.3390/genes10100759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826490PMC
September 2019

cindr, the Drosophila Homolog of the CD2AP Alzheimer's Disease Risk Gene, Is Required for Synaptic Transmission and Proteostasis.

Cell Rep 2019 08;28(7):1799-1813.e5

Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

The Alzheimer's disease (AD) susceptibility gene, CD2-associated protein (CD2AP), encodes an actin binding adaptor protein, but its function in the nervous system is largely unknown. Loss of the Drosophila ortholog cindr enhances neurotoxicity of human Tau, which forms neurofibrillary tangle pathology in AD. We show that Cindr is expressed in neurons and present at synaptic terminals. cindr mutants show impairments in synapse maturation and both synaptic vesicle recycling and release. Cindr associates and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and the plasma membrane calcium ATPase (PMCA). Loss of cindr elevates PMCA levels and reduces cytosolic calcium. Studies of Cd2ap null mice support a conserved role in synaptic proteostasis, and CD2AP protein levels are inversely related to Synapsin abundance in human postmortem brains. Our results reveal CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure and function.
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http://dx.doi.org/10.1016/j.celrep.2019.07.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703184PMC
August 2019

Sensitized genetic backgrounds reveal differential roles for EGF repeat xylosyltransferases in Drosophila Notch signaling.

Glycobiology 2018 11;28(11):849-859

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

In multicellular organisms, glycosylation regulates various developmental signaling pathways including the Notch pathway. One of the O-linked glycans added to epidermal growth factor-like (EGF) repeats in animal proteins including the Notch receptors is the xylose-xylose-glucose-O oligosaccharide. Drosophila glucoside xylosyltransferase (Gxylt) Shams negatively regulates Notch signaling in specific contexts. Since Shams adds the first xylose residue to O-glucose, its loss-of-function phenotype could be due to the loss of the first xylose, the second xylose or both. To examine the contribution of the second xylose residues to Drosophila Notch signaling, we have performed biochemical and genetic analysis on CG11388, which is the Drosophila homolog of human xyloside xylosyltransferase 1 (XXYLT1). Experiments in S2 cells indicated that similar to human XXYLT1, CG11388 can add the second xylose to xylose-glucose-O glycans. Flies lacking both copies of CG11388 (Xxylt) are viable and fertile and do not show gross phenotypes indicative of altered Notch signaling. However, genetic interaction experiments show that in sensitized genetic backgrounds with decreased or increased Notch pathway components, loss of Xxylt promotes Delta-mediated activation of Notch. Unexpectedly, we find that in such sensitized backgrounds, even loss of one copy of the fly Gxylt shams enhances Delta-mediated Notch activation. Taken together, these data indicate that while the first xylose plays a key role in tuning the Delta-mediated Notch signaling in Drosophila, the second xylose has a fine-tuning role only revealed in sensitized genetic backgrounds.
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http://dx.doi.org/10.1093/glycob/cwy080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454539PMC
November 2018

Xylosylation of the Notch receptor preserves the balance between its activation by trans-Delta and inhibition by cis-ligands in Drosophila.

PLoS Genet 2017 04 10;13(4):e1006723. Epub 2017 Apr 10.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.

The Drosophila glucoside xylosyltransferase Shams xylosylates Notch and inhibits Notch signaling in specific contexts including wing vein development. However, the molecular mechanisms underlying context-specificity of the shams phenotype is not known. Considering the role of Delta-Notch signaling in wing vein formation, we hypothesized that Shams might affect Delta-mediated Notch signaling in Drosophila. Using genetic interaction studies, we find that altering the gene dosage of Delta affects the wing vein and head bristle phenotypes caused by loss of Shams or by mutations in the Notch xylosylation sites. Clonal analysis suggests that loss of shams promotes Delta-mediated Notch activation. Further, Notch trans-activation by ectopically overexpressed Delta shows a dramatic increase upon loss of shams. In agreement with the above in vivo observations, cell aggregation and ligand-receptor binding assays show that shams knock-down in Notch-expressing cells enhances the binding between Notch and trans-Delta without affecting the binding between Notch and trans-Serrate and cell surface levels of Notch. Loss of Shams does not impair the cis-inhibition of Notch by ectopic overexpression of ligands in vivo or the interaction of Notch and cis-ligands in S2 cells. Nevertheless, removing one copy of endogenous ligands mimics the effects of loss shams on Notch trans-activation by ectopic Delta. This favors the notion that trans-activation of Notch by Delta overcomes the cis-inhibition of Notch by endogenous ligands upon loss of shams. Taken together, our data suggest that xylosylation selectively impedes the binding of Notch with trans-Delta without affecting its binding with cis-ligands and thereby assists in determining the balance of Notch receptor's response to cis-ligands vs. trans-Delta during Drosophila development.
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http://dx.doi.org/10.1371/journal.pgen.1006723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402982PMC
April 2017

A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss.

EMBO Mol Med 2016 11 2;8(11):1289-1309. Epub 2016 Nov 2.

Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain

Skeletal muscle regeneration by muscle satellite cells is a physiological mechanism activated upon muscle damage and regulated by Notch signaling. In a family with autosomal recessive limb-girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function. In vitro and in vivo experiments demonstrated that the mutation reduces O-glucosyltransferase activity on Notch and impairs muscle development. Muscles from patients revealed decreased Notch signaling, dramatic reduction in satellite cell pool and a muscle-specific α-dystroglycan hypoglycosylation not present in patients' fibroblasts. Primary myoblasts from patients showed slow proliferation, facilitated differentiation, and a decreased pool of quiescent PAX7 cells. A robust rescue of the myogenesis was demonstrated by increasing Notch signaling. None of these alterations were found in muscles from secondary dystroglycanopathy patients. These data suggest that a key pathomechanism for this novel form of muscular dystrophy is Notch-dependent loss of satellite cells.
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http://dx.doi.org/10.15252/emmm.201505815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5090660PMC
November 2016

The protein O-glucosyltransferase Rumi modifies eyes shut to promote rhabdomere separation in Drosophila.

PLoS Genet 2014 Nov 20;10(11):e1004795. Epub 2014 Nov 20.

Program in Genes & Development, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, United States of America; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.

The protein O-glucosyltransferase Rumi/POGLUT1 regulates Drosophila Notch signaling by adding O-glucose residues to the Notch extracellular domain. Rumi has other predicted targets including Crumbs (Crb) and Eyes shut (Eys), both of which are involved in photoreceptor development. However, whether Rumi is required for the function of Crb and Eys remains unknown. Here we report that in the absence of Rumi or its enzymatic activity, several rhabdomeres in each ommatidium fail to separate from one another in a Notch-independent manner. Mass spectral analysis indicates the presence of O-glucose on Crb and Eys. However, mutating all O-glucosylation sites in a crb knock-in allele does not cause rhabdomere attachment, ruling out Crb as a biologically-relevant Rumi target in this process. In contrast, eys and rumi exhibit a dosage-sensitive genetic interaction. In addition, although in wild-type ommatidia most of the Eys protein is found in the inter-rhabdomeral space (IRS), in rumi mutants a significant fraction of Eys remains in the photoreceptor cells. The intracellular accumulation of Eys and the IRS defect worsen in rumi mutants raised at a higher temperature, and are accompanied by a ∼50% decrease in the total level of Eys. Moreover, removing one copy of an endoplasmic reticulum chaperone enhances the rhabdomere attachment in rumi mutant animals. Altogether, our data suggest that O-glucosylation of Eys by Rumi ensures rhabdomere separation by promoting proper Eys folding and stability in a critical time window during the mid-pupal stage. Human EYS, which is mutated in patients with autosomal recessive retinitis pigmentosa, also harbors multiple Rumi target sites. Therefore, the role of O-glucose in regulating Eys may be conserved.
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http://dx.doi.org/10.1371/journal.pgen.1004795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4238978PMC
November 2014

Fringe proteins modulate Notch-ligand cis and trans interactions to specify signaling states.

Elife 2014 Sep 25;3:e02950. Epub 2014 Sep 25.

Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States.

The Notch signaling pathway consists of multiple types of receptors and ligands, whose interactions can be tuned by Fringe glycosyltransferases. A major challenge is to determine how these components control the specificity and directionality of Notch signaling in developmental contexts. Here, we analyzed same-cell (cis) Notch-ligand interactions for Notch1, Dll1, and Jag1, and their dependence on Fringe protein expression in mammalian cells. We found that Dll1 and Jag1 can cis-inhibit Notch1, and Fringe proteins modulate these interactions in a way that parallels their effects on trans interactions. Fringe similarly modulated Notch-ligand cis interactions during Drosophila development. Based on these and previously identified interactions, we show how the design of the Notch signaling pathway leads to a restricted repertoire of signaling states that promote heterotypic signaling between distinct cell types, providing insight into the design principles of the Notch signaling system, and the specific developmental process of Drosophila dorsal-ventral boundary formation.
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http://dx.doi.org/10.7554/eLife.02950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174579PMC
September 2014

Negative regulation of notch signaling by xylose.

PLoS Genet 2013 Jun 6;9(6):e1003547. Epub 2013 Jun 6.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

The Notch signaling pathway controls a large number of processes during animal development and adult homeostasis. One of the conserved post-translational modifications of the Notch receptors is the addition of an O-linked glucose to epidermal growth factor-like (EGF) repeats with a C-X-S-X-(P/A)-C motif by Protein O-glucosyltransferase 1 (POGLUT1; Rumi in Drosophila). Genetic experiments in flies and mice, and in vivo structure-function analysis in flies indicate that O-glucose residues promote Notch signaling. The O-glucose residues on mammalian Notch1 and Notch2 proteins are efficiently extended by the addition of one or two xylose residues through the function of specific mammalian xylosyltransferases. However, the contribution of xylosylation to Notch signaling is not known. Here, we identify the Drosophila enzyme Shams responsible for the addition of xylose to O-glucose on EGF repeats. Surprisingly, loss- and gain-of-function experiments strongly suggest that xylose negatively regulates Notch signaling, opposite to the role played by glucose residues. Mass spectrometric analysis of Drosophila Notch indicates that addition of xylose to O-glucosylated Notch EGF repeats is limited to EGF14-20. A Notch transgene with mutations in the O-glucosylation sites of Notch EGF16-20 recapitulates the shams loss-of-function phenotypes, and suppresses the phenotypes caused by the overexpression of human xylosyltransferases. Antibody staining in animals with decreased Notch xylosylation indicates that xylose residues on EGF16-20 negatively regulate the surface expression of the Notch receptor. Our studies uncover a specific role for xylose in the regulation of the Drosophila Notch signaling, and suggest a previously unrecognized regulatory role for EGF16-20 of Notch.
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http://dx.doi.org/10.1371/journal.pgen.1003547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675014PMC
June 2013

Drosophila IAP1-mediated ubiquitylation controls activation of the initiator caspase DRONC independent of protein degradation.

PLoS Genet 2011 Sep 1;7(9):e1002261. Epub 2011 Sep 1.

Department of Biochemistry and Molecular Biology, Genes and Development Graduate Program, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

Ubiquitylation targets proteins for proteasome-mediated degradation and plays important roles in many biological processes including apoptosis. However, non-proteolytic functions of ubiquitylation are also known. In Drosophila, the inhibitor of apoptosis protein 1 (DIAP1) is known to ubiquitylate the initiator caspase DRONC in vitro. Because DRONC protein accumulates in diap1 mutant cells that are kept alive by caspase inhibition ("undead" cells), it is thought that DIAP1-mediated ubiquitylation causes proteasomal degradation of DRONC, protecting cells from apoptosis. However, contrary to this model, we show here that DIAP1-mediated ubiquitylation does not trigger proteasomal degradation of full-length DRONC, but serves a non-proteolytic function. Our data suggest that DIAP1-mediated ubiquitylation blocks processing and activation of DRONC. Interestingly, while full-length DRONC is not subject to DIAP1-induced degradation, once it is processed and activated it has reduced protein stability. Finally, we show that DRONC protein accumulates in "undead" cells due to increased transcription of dronc in these cells. These data refine current models of caspase regulation by IAPs.
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http://dx.doi.org/10.1371/journal.pgen.1002261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164697PMC
September 2011

Regulation of notch signaling via O-glucosylation insights from Drosophila studies.

Methods Enzymol 2010 ;480:375-98

Brown Foundation Institute of Molecular Medicine (IMM), Department of Biochemistry & Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

Recent work using Drosophila melanogaster has shown that a protein O-glucosyltransferase called Rumi regulates Notch signaling. Studies on several alleles of rumi identified in a forward genetic screen indicated that Rumi is a temperature-sensitive regulator of Notch signaling in flies. Further genetic and rescue experiments demonstrated that Rumi is a general regulator of Drosophila Notch signaling. Biochemical analyses showed that Rumi adds glucose to specific EGF repeats in the extracellular domain of Notch receptor in the Drosophila S2 cell line. Furthermore, RNAi-mediated knockdown of Rumi in this cell line resulted in a severe decrease in the level of O-linked glucose on Notch. In this chapter, we discuss the genetic and biochemical methods used to determine the role of Rumi in the regulation of Notch signaling in flies.
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http://dx.doi.org/10.1016/S0076-6879(10)80017-5DOI Listing
December 2010

Genetic control of programmed cell death (apoptosis) in Drosophila.

Fly (Austin) 2009 Jan-Mar;3(1):78-90. Epub 2009 Jan 8.

The University of Texas MD Anderson Cancer Center, The Genes and Development Graduate Program, Department of Biochemistry and Molecular Biology, Houston, Texas 77030, USA.

Programmed cell death, or apoptosis, is a highly conserved cellular process that has been intensively investigated in nematodes, flies and mammals. The genetic conservation, the low redundancy, the feasibility for high-throughput genetic screens and the identification of temporally and spatially regulated apoptotic responses make Drosophila melanogaster a great model for the study of apoptosis. Here, we review the key players of the cell death pathway in Drosophila and discuss their roles in apoptotic and non-apoptotic processes.
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http://dx.doi.org/10.4161/fly.3.1.7800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702463PMC
September 2009

Inactivation of effector caspases through nondegradative polyubiquitylation.

Mol Cell 2008 Nov;32(4):540-53

The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, UK.

Ubiquitin-mediated inactivation of caspases has long been postulated to contribute to the regulation of apoptosis. However, detailed mechanisms and functional consequences of caspase ubiquitylation have not been demonstrated. Here we show that the Drosophila Inhibitor of Apoptosis 1, DIAP1, blocks effector caspases by targeting them for polyubiquitylation and nonproteasomal inactivation. We demonstrate that the conjugation of ubiquitin to drICE suppresses its catalytic potential in cleaving caspase substrates. Our data suggest that ubiquitin conjugation sterically interferes with substrate entry and reduces the caspase's proteolytic velocity. Disruption of drICE ubiquitylation, either by mutation of DIAP1's E3 activity or drICE's ubiquitin-acceptor lysines, abrogates DIAP1's ability to neutralize drICE and suppress apoptosis in vivo. We also show that DIAP1 rests in an "inactive" conformation that requires caspase-mediated cleavage to subsequently ubiquitylate caspases. Taken together, our findings demonstrate that effector caspases regulate their own inhibition through a negative feedback mechanism involving DIAP1 "activation" and nondegradative polyubiquitylation.
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http://dx.doi.org/10.1016/j.molcel.2008.09.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713662PMC
November 2008

The E1 ubiquitin-activating enzyme Uba1 in Drosophila controls apoptosis autonomously and tissue growth non-autonomously.

Development 2008 Jan 28;135(1):43-52. Epub 2007 Nov 28.

The University of Texas M D Anderson Cancer Center, Department of Biochemistry and Molecular Biology, Houston, TX 77030, USA.

Ubiquitination is an essential process regulating turnover of proteins for basic cellular processes such as the cell cycle and cell death (apoptosis). Ubiquitination is initiated by ubiquitin-activating enzymes (E1), which activate and transfer ubiquitin to ubiquitin-conjugating enzymes (E2). Conjugation of target proteins with ubiquitin is then mediated by ubiquitin ligases (E3). Ubiquitination has been well characterized using mammalian cell lines and yeast genetics. However, the consequences of partial or complete loss of ubiquitin conjugation in a multi-cellular organism are not well understood. Here, we report the characterization of Uba1, the only E1 in Drosophila. We found that weak and strong Uba1 alleles behave genetically differently with sometimes opposing phenotypes. Whereas weak Uba1 alleles protect cells from cell death, clones of strong Uba1 alleles are highly apoptotic. Strong Uba1 alleles cause cell cycle arrest which correlates with failure to reduce cyclin levels. Surprisingly, clones of strong Uba1 mutants stimulate neighboring wild-type tissue to undergo cell division in a non-autonomous manner giving rise to overgrowth phenotypes of the mosaic fly. We demonstrate that the non-autonomous overgrowth is caused by failure to downregulate Notch signaling in Uba1 mutant clones. In summary, the phenotypic analysis of Uba1 demonstrates that impaired ubiquitin conjugation has significant consequences for the organism, and may implicate Uba1 as a tumor suppressor gene.
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http://dx.doi.org/10.1242/dev.011288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277323PMC
January 2008

Mis-specified cells die by an active gene-directed process, and inhibition of this death results in cell fate transformation in Drosophila.

Development 2005 Dec 9;132(24):5343-52. Epub 2005 Nov 9.

The University of Texas M.D. Anderson Cancer Center, Department of Biochemistry and Molecular Biology, 1515 Holcombe Boulevard, Unit 1000, Houston, TX 77030, USA.

Incorrectly specified or mis-specified cells often undergo cell death or are transformed to adopt a different cell fate during development. The underlying cause for this distinction is largely unknown. In many developmental mutants in Drosophila, large numbers of mis-specified cells die synchronously, providing a convenient model for analysis of this phenomenon. The maternal mutant bicoid is particularly useful model with which to address this issue because its mutant phenotype is a combination of both transformation of tissue (acron to telson) and cell death in the presumptive head and thorax regions. We show that a subset of these mis-specified cells die through an active gene-directed process involving transcriptional upregulation of the cell death inducer hid. Upregulation of hid also occurs in oskar mutants and other segmentation mutants. In hid bicoid double mutants, mis-specified cells in the presumptive head and thorax survive and continue to develop, but they are transformed to adopt a different cell fate. We provide evidence that the terminal torso signaling pathway protects the mis-specified telson tissue in bicoid mutants from hid-induced cell death, whereas mis-specified cells in the head and thorax die, presumably because equivalent survival signals are lacking. These data support a model whereby mis-specification can be tolerated if a survival pathway is provided, resulting in cellular transformation.
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http://dx.doi.org/10.1242/dev.02150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760325PMC
December 2005

Genetic control of programmed cell death in Drosophila melanogaster.

Semin Cell Dev Biol 2005 Apr;16(2):225-35

The University of Texas, MD Anderson Cancer Center, Department of Biochemistry and Molecular Biology, The Genes and Development Graduate Program, Houston, TX 77030, USA.

Apoptosis is a genetically controlled form of cell death that is an important feature of animal development and homeostasis. The genes involved in the control and execution of apoptosis are conserved throughout evolution. However, the actual molecular mechanisms used by these genes vary from species to species. In this review, we focus on the genetic components of apoptosis in the fruit fly Drosophila melanogaster, and compare their mode of action to the one employed by the homologous genes in mammals. We also cover recent advances that show that apoptotic genes have a requirement in processes other than apoptosis.
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http://dx.doi.org/10.1016/j.semcdb.2005.01.002DOI Listing
April 2005

Helper peptide G89 (HER-2:777-789) and G89-activated cells regulate the survival of effectors induced by the CTL epitope E75 (HER-2, 369-377). Correlation with the IFN-gamma: IL-10 balance.

Anticancer Res 2002 May-Jun;22(3):1481-90

Department of Gynecologic Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.

The CTL response to Ag expands after priming and subsequently contracts reducing the number of effectors. CD4+ cells are described as regulators of CTL immunity. To elucidate whether CD4+ cells are involved in survival of effector CTL and the survival signals, we used CTL and Th peptides form the HER-2 protooncogene recognized in association with HL-A2 and HLA-DR4, respectively. We analyzed the effect of cells stimulated with G89 (777-789) in survival and expression of lytic function of CTL specific for the epitope E75 (369-377). G89 primed cells (G89-PR) and G89 enhanced expansion and Ag-specific cytolyis of CTL at priming with E75, but inhibited survival of E75-specific CTL at restimulation. These effects were not simply a reflection of the increases in IFN-gamma and IL-10, but the ratio IFN-gamma/lL-10 modified by G89 differentially regulated the survival of stimulated cells. This suggests that the use of helper antigens in cancer vaccines should be evaluated in the context of their CTL survival inducing effect.
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September 2002
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