Michael A White

University of Texas Southwestern Medical Center, Dallas, Texas, United States

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Publications (91)846.02 Total impact

  • Richard J Wang · Michael A White · Bret A Payseur
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    ABSTRACT: Hybrids between species are often sterile or inviable. This form of reproductive isolation is thought to evolve via the accumulation of mutations that interact to reduce fitness when combined in hybrids. Mathematical formulations of this "Dobzhansky-Muller model" predict an accelerating buildup of hybrid incompatibilities with divergence time (the "snowball effect"). Although the Dobzhansky-Muller model is widely accepted, the snowball effect has only been tested in two species groups. We evaluated evidence for the snowball effect in the evolution of hybrid male sterility among subspecies of house mice, a recently diverged group that shows partial reproductive isolation. We compared the history of subspecies divergence with patterns of quantitative trait loci (QTL) detected in F2 intercrosses between two pairs of subspecies (Mus musculus domesticus with M. m. musculus and M. m. domesticus with M. m. castaneus). We used a recently developed phylogenetic comparative method to statistically measure the fit of this data to the snowball prediction. To apply this method, QTL were partitioned as either shared or unshared in the two crosses. A heuristic partitioning based on the overlap of QTL confidence intervals produced unambiguous support for the snowball effect. An alternative approach combining data among crosses favored the snowball effect for the autosomes, but a linear accumulation of incompatibilities for the X chromosome. Reasoning that the X chromosome analyses are complicated by low mapping resolution, we conclude that hybrid male sterility loci have snowballed in house mice. Our study illustrates the power of comparative genetic mapping for understanding mechanisms of speciation. Copyright © 2015, The Genetics Society of America.
    Genetics 07/2015; DOI:10.1534/genetics.115.179499 · 4.87 Impact Factor
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    ABSTRACT: Modern cancer treatment employs many effective chemotherapeutic agents originally discovered from natural sources. The cyclic depsipeptide didemnin B has demonstrated impressive anticancer activity in preclinical models. Clinical use has been approved but is limited by sparse patient responses combined with toxicity risk and an unclear mechanism of action. From a broad-scale effort to match antineoplastic natural products to their cellular activities, we found that didemnin B selectively induces rapid and wholesale apoptosis through dual inhibition of PPT1 and EEF1A1. Furthermore, empirical discovery of a small panel of exceptional responders to didemnin B allowed the generation of a regularized regression model to extract a sparse-feature genetic biomarker capable of predicting sensitivity to didemnin B. This may facilitate patient selection in a fashion that could enhance and expand the therapeutic application of didemnin B against neoplastic disease.
    Nature Chemical Biology 04/2015; 11(6). DOI:10.1038/nchembio.1797 · 13.22 Impact Factor
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and insights into both disease etiology and targeted intervention are needed. A total of 109 micro-dissected PDA cases were subjected to whole-exome sequencing. Microdissection enriches tumour cellularity and enhances mutation calling. Here we show that environmental stress and alterations in DNA repair genes associate with distinct mutation spectra. Copy number alterations target multiple tumour suppressive/oncogenic loci; however, amplification of MYC is uniquely associated with poor outcome and adenosquamous subtype. We identify multiple novel mutated genes in PDA, with select genes harbouring prognostic significance. RBM10 mutations associate with longer survival in spite of histological features of aggressive disease. KRAS mutations are observed in >90% of cases, but codon Q61 alleles are selectively associated with improved survival. Oncogenic BRAF mutations are mutually exclusive with KRAS and define sensitivity to vemurafenib in PDA models. High-frequency alterations in Wnt signalling, chromatin remodelling, Hedgehog signalling, DNA repair and cell cycle processes are observed. Together, these data delineate new genetic diversity of PDA and provide insights into prognostic determinants and therapeutic targets.
    Nature Communications 04/2015; 6:6744. DOI:10.1038/ncomms7744 · 10.74 Impact Factor
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    ABSTRACT: AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy status. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes to regain energy homeostasis. Cancer cells can occasionally suppress the growth-restrictive AMPK pathway by mutation of an upstream regulatory kinase. Here, we describe a widespread mechanism to suppress AMPK through its ubiquitination and degradation by the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase. MAGE-A3 and MAGE-A6 are highly similar proteins normally expressed only in the male germline but frequently re-activated in human cancers. MAGE-A3/6 are necessary for cancer cell viability and are sufficient to drive tumorigenic properties of non-cancerous cells. Screening for targets of MAGE-A3/6-TRIM28 revealed that it ubiquitinates and degrades AMPKα1. This leads to inhibition of autophagy, activation of mTOR signaling, and hypersensitization to AMPK agonists, such as metformin. These findings elucidate a germline mechanism commonly hijacked in cancer to suppress AMPK. Copyright © 2015 Elsevier Inc. All rights reserved.
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    ABSTRACT: Lung cancer is the leading cause of cancer-related fatalities. Recent success developing genotypically-targeted therapies, with potency only in well-defined subpopulations of tumors, suggests a path to improving patient survival. We utilized a library of oligonucleotide inhibitors to microRNAs, a class of post-transcriptional gene regulators, to identify novel synthetic lethal interactions between miRNA inhibition and molecular mechanisms in NSCLC. Two inhibitors, those for miR-92a and miR-1226*, produced a toxicity distribution across a panel of 27 cell lines that correlated with loss of p53 protein expression. Notably, depletion of p53 was sufficient to confer sensitivity to otherwise resistant telomerase-immortalized bronchial epithelial cells. We found that both miR inhibitors cause sequence-specific down-regulation of the miR-17~92 polycistron, and this down-regulation was toxic only in the context of p53 loss. Mechanistic studies indicated the selective toxicity of miR-17~92 polycistron inactivation was the consequence of derepression of vitamin D signaling via suppression of CYP24A1; a rate limiting enzyme in the 1α,25-dihydroxyvitamin D3 metabolic pathway. Of note, high CYP24A1 expression significantly correlated with poor patient outcome in multiple lung cancer cohorts. Our results indicate that the screening approach utilized in this study can identify clinically relevant synthetic lethal interactions, and that vitamin D receptor agonists may show enhanced efficacy in p53-negative lung cancer patients. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014; 75(4). DOI:10.1158/0008-5472.CAN-14-1329 · 9.28 Impact Factor
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    ABSTRACT: KRAS mutation, which occurs in ∼95% of pancreatic ductal adenocarcinoma (PDA), has been shown to program tumor metabolism. MCT4 is highly upregulated in a subset of PDA with a glycolytic gene expression program and poor survival. Models with high levels of MCT4 preferentially employ glycolytic metabolism. Selectively in such "addicted" models, MCT4 attenuation compromised glycolytic flux with compensatory induction of oxidative phosphorylation and scavenging of metabolites by macropinocytosis and autophagy. In spite of these adaptations, MCT4 depletion induced cell death characterized by elevated reactive oxygen species and metabolic crisis. Cell death induced by MCT4-depletion was augmented by inhibition of compensatory pathways. In xenograft models, MCT4 had a significant impact on tumor metabolism and was required for rapid tumor growth. Together, these findings illustrate the metabolic diversity of PDA described by MCT4, delineate pathways through which this lactate transporter supports cancer growth, and demonstrate that PDA can be rationally targeted based on metabolic addictions. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
  • Molecular Cancer Research 12/2014; 12(12 Supplement):A04-A04. DOI:10.1158/1557-3125.RASONC14-A04 · 4.50 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) have been shown to regulate viral infection, but the miRNAs that target intracellular sensors and adaptors of innate immunity have not been fully uncovered. Here we conduct an miRNA mimic screen and validation with miRNA inhibitors in cells infected with vesicular stomatitis virus (VSV) to identify miRNAs that regulate viral-host interactions. We identify miR-576-3p as a robust regulator of infection by VSV and other RNA and DNA viruses. While an miR-576-3p mimic sensitizes cells to viral replication, inhibition of endogenous miR-576-3p prevents infection. miR-576-3p is induced by IRF3 concomitantly with interferon and targets STING, MAVS and TRAF3, which are critical factors for interferon expression. Interestingly, miR-576-3p and its binding sites are primate-specific and miR-576-3p levels are reduced in inflammatory diseases. These findings indicate that induction of miR-576-3p by IRF3 triggers a feedback mechanism to reduce interferon expression and set an antiviral response threshold to likely avoid excessive inflammation.
    Nature Communications 09/2014; 5:4963. DOI:10.1038/ncomms5963 · 10.74 Impact Factor
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    Banu Eskiocak · Aktar Ali · Michael A White
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    ABSTRACT: XCT 790 is widely used to inhibit estrogen-related receptor alpha (ERRα) activity as an inverse agonist. Here, we report that XCT 790 potently activates AMP kinase (AMPK), in a dose-dependent and ERRα independent manner, with active concentrations more than 25-fold below those typically used to perturb ERRα. AMPK activation is secondary to inhibition of energy production as XCT 790 rapidly depletes cellular ATP. A concomitant increase in oxygen consumption rates suggests uncoupling of the mitochondrial electron transport chain. Consistent with this, XCT 790 decreased mitochondrial membrane potential without affecting mitochondrial mass. Therefore, XCT 790 is a potent, fast acting, mitochondrial uncoupler independent of its inhibition of ERRα. The biological activity together with structural features in common with the chemical uncouplers FCCP and CCCP indicate likely mode of action as a proton ionophore.
    Biochemistry 07/2014; 53(29). DOI:10.1021/bi500737n · 3.01 Impact Factor
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    ABSTRACT: A challenge for large-scale siRNA loss-of-function studies is the biological pleiotropy resulting from multiple modes of action of siRNA reagents. A major confounding feature of these reagents is the microRNA-like translational quelling resulting from short regions of oligonucleotide complementarity to many different messenger RNAs. We developed a computational approach, deconvolution analysis of RNAi screening data, for automated quantitation of off-target effects in RNAi screening data sets. Substantial reduction of off-target rates was experimentally validated in five distinct biological screens across different genome-wide siRNA libraries. A public-access graphical-user-interface has been constructed to facilitate application of this algorithm.
    Nucleic Acids Research 06/2014; 42(13). DOI:10.1093/nar/gku306 · 9.11 Impact Factor
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    05/2014; 2(Suppl 1):P13. DOI:10.1186/2049-3002-2-S1-P13
  • Cancer Research 05/2014; 73(19 Supplement):C16-C16. DOI:10.1158/1538-7445.FBCR13-C16 · 9.28 Impact Factor
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    ABSTRACT: RASSF1A is one of the most frequently inactivated genes in over 30 different types of cancers (1). Despite the prevalence of RASSF1A silencing in human cancer, the mechanism by which RASSF1A functions as a tumor suppressor is not well understood. Characterization of the consequences of RASSF1A loss on epithelial cell proliferation revealed that RASSF1A expression suppresses both miR-21 expression and ERK1/2 kinase activation. The mechanism of the former is through restraint of SCF(ßTrCP) -dependent destruction of the REST tumor suppressor, and consequent inhibition of miR-21 promoter activation. The mechanism of the latter is through physical sequestration of MST2, which results in accumulation of inactivating S259 phosphorylation of RAF1. Whether or not inactivation of these RASSF1A regulatory relationships can unleash enhanced proliferative capacity is dependent upon the coupling of SCF(ßTrCP) and miR-21 to suppression of SKP2 protein translation and stability. Airway epithelial cultures retain this coupling and therefore respond to RASSF1A inactivation by p27-dependent cell cycle arrest. In contrast, colonic crypt-derived epithelial cells have uncoupled SCF(ßTrCP) from SKP2 and respond to RASSF1A inactivation by enhanced proliferation rates. These observations help account for context-specific molecular etiology of oncogenic transformation, and suggest intervention strategies for recently developed SKP2 inhibitors.
    Molecular and Cellular Biology 04/2014; 34(12). DOI:10.1128/MCB.01506-13 · 5.04 Impact Factor
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    ABSTRACT: Island populations provide natural laboratories for studying key contributors to evolutionary change, including natural selection, population size, and the colonization of new environments. The demographic histories of island populations can be reconstructed from patterns of genetic diversity. House mice (Mus musculus) inhabit islands throughout the globe, making them an attractive system for studying island colonization from a genetic perspective. Gough Island, in the central South Atlantic Ocean, is one of the remotest islands in the world. House mice were introduced to Gough Island by sealers during the 19th century, and display unusual phenotypes, including exceptionally large body size and carnivorous feeding behavior. We describe genetic variation in Gough Island mice using mitochondrial sequences, nuclear sequences, and microsatellites. Phylogenetic analysis of mitochondrial sequences suggested that Gough Island mice belong to Mus musculus domesticus, with the maternal lineage possibly originating in England or France. Cluster analyses of microsatellites revealed genetic membership for Gough Island mice in multiple coastal populations in Western Europe, suggesting admixed ancestry. Gough Island mice showed substantial reductions in mitochondrial and nuclear sequence variation and weak reductions in microsatellite diversity compared with Western European populations, consistent with a population bottleneck. Approximate Bayesian Computation (ABC) estimated that mice recently colonized Gough Island (~100 years ago) and experienced a 98% reduction in population size followed by a rapid expansion. Our results indicate that the unusual phenotypes of Gough Island mice evolved rapidly, positioning these mice as useful models for understanding rapid phenotypic evolution. This article is protected by copyright. All rights reserved.
    Molecular Ecology 03/2014; 23(1923):1939. DOI:10.1111/mec.12715 · 6.49 Impact Factor
  • Amir Mor · Michael A White · Beatriz Ma Fontoura
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    ABSTRACT: In eukaryotic cells, the cytoplasm and the nucleus are separated by a double-membraned nuclear envelope (NE). Thus, transport of molecules between the nucleus and the cytoplasm occurs via gateways termed the nuclear pore complexes (NPCs), which are the largest intracellular channels in nature. While small molecules can passively translocate through the NPC, large molecules are actively imported into the nucleus by interacting with receptors that bind nuclear pore complex proteins (Nups). Regulatory factors then function in assembly and disassembly of transport complexes. Signaling pathways, cell cycle, pathogens, and other physiopathological conditions regulate various constituents of the nuclear transport machinery. Here, we will discuss several findings related to modulation of nuclear transport during physiological and pathological conditions, including tumorigenesis, viral infection, and congenital syndrome. We will also explore chemical biological approaches that are being used as probes to reveal new mechanisms that regulate nucleocytoplasmic trafficking and that are serving as starting points for drug development.
    Current opinion in cell biology 02/2014; 28C(1):28-35. DOI:10.1016/j.ceb.2014.01.007 · 8.74 Impact Factor
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    Leslie M Turner · Michael A White · Diethard Tautz · Bret A Payseur
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    ABSTRACT: Hybrid dysfunction, a common feature of reproductive barriers between species, is often caused by negative epistasis between loci ("Dobzhansky-Muller incompatibilities"). The nature and complexity of hybrid incompatibilities remain poorly understood because identifying interacting loci that affect complex phenotypes is difficult. With subspecies in the early stages of speciation, an array of genetic tools, and detailed knowledge of reproductive biology, house mice (Mus musculus) provide a model system for dissecting hybrid incompatibilities. Male hybrids between M. musculus subspecies often show reduced fertility. Previous studies identified loci and several X chromosome-autosome interactions that contribute to sterility. To characterize the genetic basis of hybrid sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven 'hotspots,' seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL-but not cis eQTL-were substantially lower when mapping was restricted to a 'fertile' subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility. The integrated mapping approach we employed is applicable in a broad range of organisms and we advocate for widespread adoption of a network-centered approach in speciation genetics.
    PLoS Genetics 02/2014; 10(2):e1004162. DOI:10.1371/journal.pgen.1004162 · 8.17 Impact Factor
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    ABSTRACT: Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology.
    Cell 10/2013; 155(3):552-66. DOI:10.1016/j.cell.2013.09.041 · 33.12 Impact Factor
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    ABSTRACT: A challenge for biomedical research is the development of pharmaceuticals that appropriately target disease mechanisms. Natural products can be a rich source of bioactive chemicals for medicinal applications but can act through unknown mechanisms and can be difficult to produce or obtain. To address these challenges, we developed a new marine-derived, renewable natural products resource and a method for linking bioactive derivatives of this library to the proteins and biological processes that they target in cells. We used cell-based screening and computational analysis to match gene expression signatures produced by natural products to those produced by small interfering RNA (siRNA) and synthetic microRNA (miRNA) libraries. With this strategy, we matched proteins and miRNAs with diverse biological processes and also identified putative protein targets and mechanisms of action for several previously undescribed marine-derived natural products. We confirmed mechanistic relationships for selected siRNAs, miRNAs, and compounds with functional roles in autophagy, chemotaxis mediated by discoidin domain receptor 2, or activation of the kinase AKT. Thus, this approach may be an effective method for screening new drugs while simultaneously identifying their targets.
    Science Signaling 10/2013; 6(297):ra90. DOI:10.1126/scisignal.2004657 · 7.65 Impact Factor
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    ABSTRACT: Melanoma is a highly aggressive malignant tumor of melanocyte for which treatment options have been scarce to date. Here, using high throughput cell-based screening of a large chemical compound file, we are isolating synthetic small molecules that are toxic against metastatic melanoma cells. We identified a methoxyphenyl-oxadiazole (SW174769) to be a promising candidate. SW174769 induced cell death in 15 of 19 melanoma cell lines with IC50s between 2.5 to 8 uM, but showed no detectable toxicity to normal melanocytes, human bronchial epithelial cells or majority of the non-small cell lung cancer cells with doses as high as 50uM. These results suggest that the toxicity of SW174769 may be limited to cancer cells with melanocytic origin and hence indicate the potential for a large therapeutic window. Small modifications in the structure of the compound caused a huge drop in the overall efficacy indicating the requirement of an alkyne functional group for toxic effects. Mode-of-action studies indicate SW174769 induces apoptosis concomitant with, but independent of, stabilization of p53. This SW174769 caused apoptosis indicated by an increase in caspase 3/7 activity. Correlation analysis with genomic features identified a gene expression signature predictive of response to SW174769. Current studies are focused on chemical development to improve potency together with target identification strategies that are compatible with low-potency chemical probes.
    International Graduate Students Immunology Conference, University of Texas Southwestern Medical Center, Dallas, Texas; 09/2013
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    ABSTRACT: Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase involved in a variety of cellular response pathways, including regulation of cell growth, proliferation, and motility. Using a newly developed platform to identify the signaling pathway/molecular target of natural products, we identified a family of alkaloid natural products, discoipyrroles A-D (1-4), from Bacillus hunanensis that inhibit the DDR2 signaling pathway. The structure of 1-4, determined by detailed two-dimensional (2D) NMR methods and confirmed by X-ray crystallographic analysis has an unusual 3H-benzo[d]pyrrolo][1,3]oxazine-3,5-dione core. Discoipyrroles A-D potently inhibit DDR2 dependent migration of BR5 fibroblasts and show selective cytotoxicity to DDR2 mutant lung cancer cell lines (IC50 120-400 nM). Examination of the biosynthesis has led to the conclusion that the discoipyrroles are formed through a nonenzymatic process, leading to a one-pot total synthesis of 1.
    Journal of the American Chemical Society 08/2013; 135(36). DOI:10.1021/ja403412y · 11.44 Impact Factor

Publication Stats

4k Citations
846.02 Total Impact Points


  • 2001–2015
    • University of Texas Southwestern Medical Center
      • • Department of Cell Biology
      • • Department of Biochemistry
      • • Department of Pharmacology
      Dallas, Texas, United States
  • 2009–2014
    • University of Wisconsin–Madison
      • Laboratory of Genetics
      Madison, Wisconsin, United States
  • 2005–2014
    • University of Texas at Dallas
      • Biochemistry
      Richardson, Texas, United States
  • 2012
    • University of California, Irvine
      Irvine, California, United States
  • 2000
    • Albert Einstein College of Medicine
      • Department of Developmental and Molecular Biology
      New York, New York, United States