Dr. Bruce A. Edgar

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Fred Hutchinson Cancer Research Center
Division of Basic Sciences
Member
University of Washington
College of Arts and Sciences
Genetics
Affiliate Professor
Professional Headshot of Bruce A. Edgar

Mailing Address

Fred Hutchinson Cancer Research Center
1100 Fairview Ave. N.
P.O. Box 19024
B2-152
Seattle, Washington 98109-1024
United States

Contact Information

Phone: (206) 667-4185
Fax: (206) 667-3308
bedgar@fhcrc.org
http://www.fhcrc.org/science/labs/edgar/index.htm

Qualifications

Ph.D., University of Washington, Genetics, 1987.

Expertise and Research Interests

The development of an animal or plant from a single egg cell involves a highly regulated program of cell growth and proliferation. Dr. Edgar's research group has focused on the genetic logic underlying Drosophila's cell proliferation program, aiming to characterize the different types of cell cycles that occur during development, identify the critical regulatory factors, and understand how these factors are in turn affected by developmental programming and environmental conditions. Recent studies have characterized the genes and pathways that control cell growth, delved into how cell growth interfaces with the cell cycle control apparatus, and addressed how developmental signaling and nutrition regulate both cell growth and cell cycle progression. We make extensive use of classical and molecular genetics, mosaic analysis, quantitative cytological assays of growth and proliferation, gene expression profiling, proteomics, and forward genetic screens. We seek to define new genes and mechanisms involved in growth control that will impact general paradigms in cell and developmental biology, and which have relevance to medical conditions involving cell and tissue growth including cancer diagnosis and therapy, stem cell biology and regeneration, wound healing, and metabolic diseases such as diabetes and obesity.

Theme 1: Developmental Control of Cell Growth

Objectives: This project has three long-term objectives: 1) To understand the cell-intrinsic mechanisms that control cell mass increase (growth); 2) To determine how cell cycle progression is coordinated with growth; and 3) To learn how patterned growth is regulated during organ morphogenesis.

Overview: This is a long-term project that has used genetic screens and candidate gene studies to identify and then characterize genes that regulate cell growth. Past studies have characterized the cellular and developmental functions of the Drosophila genes myc, pi3k, Tor, Rheb, Cyclin D, E2F, Ras, wg (a WNT), dpp (a BMP), and others. One current study is focused on Ack1, a non-receptor tyrosine kinase that we identified in a genetic screen for growth effectors. We find that Ack-1 is a dose dependent regulator of growth in many cell types, that it acts synergistically with Ras/MapK signaling, and that it promotes rampant stem cell expansion in the Drosophila gut, generating a condition similar to colon cancer. Our immediate objectives are to determine how this interesting gene controls cell growth, and to understand how it's activity is regulated during normal development in vivo. A second current study is focused on TIF-IA, a limiting regulator of rRNA synthesis that we find to be a critical growth-regulatory target of TOR signaling. Our immediate objective is to determine how nutritional signals acting via TOR regulate the function of the RNA polymerase I complex in general, and TIF-IA in particular. For both TIF-IA and Ack1, a combination of genetic and proteomic approaches are being used. Another aspect of this project is to determine how cell growth is coupled to cell cycle progression in developing Drosophila tissues. To this end we have developed a model for the control of endocycles, which are widely used in invertebrates and plants to allow cell growth. We are testing the hypothesis that growth regulators such as Myc, Tor, Ack1, and TIF-IA control rates of endocycle progression by affecting the translation of Cyclin E and E2F1, which are limiting regulators of the initiation of DNA synthesis.

Potential Impact: This work will define new genes and mechanisms involved in growth control and should impact general paradigms in cell and developmental biology. It has relevance to medical conditions involving cell and tissue growth including cancer diagnosis and therapy, regeneration, wound healing, diabetes and other metabolic diseases.

Theme 2: Growth regulatory targets of the TSC1/2 tumor suppressor complex

Objective: To identify molecular pathways via which the TSC1/2 tumor suppressor complex inhibits cell growth.

Overview: Tuberous sclerosis (TS) is an autosomal dominant disease involving widespread benign tumors and a predisposition to metastatic cancer. Most cases are caused by loss-of-heterozygosity in one of two genes, TSC1 or TSC2, which encode a protein complex. The TSC1/2 complex is thought to suppress cell growth by inhibiting Rheb, a small GTPase that is an essential activator of the Target-Of-Rapamycin (TOR) kinase. TOR in turn controls diverse metabolic processes required for cell growth including protein synthesis, nutrient import, autophagy, cytoskeletal organization, and transcription. TOR has two well-characterized targets in metazoans, S6K and 4EBP, but genetic analysis in mice and Drosophila indicate that these cannot account for the striking overgrowth phenotypes that occur when TSC function is lost. Moreover, it is unclear that all of the effects of TSC mutation are mediated by Rheb and/or TOR. Hence the identification and characterization of additional effectors of the TSC1/2 complex is required to advance our understanding of the molecular basis of this disease. This project will: 1) Identify and characterize new gene products required for TSC and Rheb function, and 2) Evaluate the hypothesis that the TSC1/2 complex mediates all of its effects via Rheb and TOR. Specific Aims are: 1) To use heavy isotope labeling and quantitative mass spectrometry (MS) to comprehensively characterize the effects of loss-of-TSC function, and gain-of-Rheb function, on the expressed proteome in Drosophila (S2) and human embryonic kidney (HEK293) cells; 2) To screen the Drosophila genome for modifiers of eye hypertrophy caused by loss of the TSC1/2 complex, or overexpression of Rheb; 3) To functionally validate potential TSC-effectors identified in Aims 1 and 2 in human cells.

Potential Impact: TSC-effector genes and pathways identified in this way are expected to be essential for the deregulation of cell growth that causes the benign tumors that plague TS patients. As such, some of these genes and pathways may constitute targets for diagnosis and treatment of the disease.

Theme 3: Growth-Regulatory targets of Cyclin D/Cdk4

Objective: To define the molecular mechanism targetted by Cyclin D/Cyclin dependent kinase 4 complexes (CycD/Cdk4) to drive cellular growth.

Overview: Deregulation of at least one component of the Ink4/Cyclin D1/retinoblastoma pathway is a common feature of most of human cancers, but the mechanism by which these genes contribute to tumorigenesis is poorly understood. Using Drosophila we discovered that Cyclin D/Cdk4 complexes, in addition to their widely appreciated function as promoters of cell cycle progression, also regulate rates of cell mass increase (growth). We discovered that CycD/Cdk4 does this by controling mitochondrial activity, via unknown targets distinct from those in the well-studied pRb/E2F pathway. We are using Drosophila genetics to identify and characterize these novel growth-regulatory targets, which we believe may be important for understanding CycD/Cdk4 function during normal and neoplastic development. Specific aims of this project comprise: 1) Identification and characterization of growth regulatory targets of CycD/Cdk4 using genome-wide screens for mutations that dominantly suppress overgrowth of the eye caused by ectopic CycD/Cdk4; 2) Identification of CycD/Cdk4 targets by gene expression profiling; 3) Characterizing the Hph/Hif-1/VHL and JAK/STAT pathways as mediators of CycD/Cdk4-driven growth; and 5) Tests to determine how CycD/Cdk4 effects mitochondrial function. Findings from Drosophila are also being validated in human cells.

Potential Impact: This project aims to elucidate how CycD/Cdk4 alters cell physiology to promote growth, and should contribute to molecular paradigms explaining how cell growth and cell division are coupled. It should also allow identification of novel Cyclin D and Ink4 targets in humans, and thus help to reveal how growth of our own cells is controlled during normal and neoplastic development. Some of the identified genes could be useful targets for cancer diagnosis or anti-cancer chemotherapeutics.

Theme 4: Developmental Control of Cell Cycle Exit

Objective: To define the molecular/genetic mechanism used to terminate cell cycle progression upon cell differentiation in the fly wing and eye.

Overview: One of the unsolved mysteries of development concerns how growth and form are controlled. The regulation of cell proliferation is central to this problem, and the mechanisms controlling cell cycle exit upon cell differentiation are particularly relevant. While cell cycle exit has been studied in cell culture and in vivo in model organisms, the mechanisms that couple differentiation signals to the cell cycle control apparatus are still poorly understood. This project aims to determine the mechanism of cell cycle exit at differentiation in the Drosophila wing and eye. Work to date has revealed that differentiation signals dominantly suppress the transcription of cell cycle control genes, including cyclin E and cdc25, via an E2F/RB-independent mechanism. Hence a current aim of this project is to analyze the transcriptional regulatory regions of these two critical cell cycle control genes to identify the cis-acting elements that mediate their silencing at differentiation. Following this, we will employ a DNA binding/quantitative proteomics approach to identify the trans-acting factors that mediate silencing of these genes at differentiation. A parallel, ongoing aim is to perform unbiased, forward genetic screens in the fly to identify novel genes involved in cell cycle exit. These approaches should identify new gene products that mediate cell cycle exit, and provide a paradigm for future studies of how differentiation signals interface with the cell cycle control apparatus to restrain cell proliferation.

Potential Impact: Cell cycle exit is critical in carcinogenesis, where it is bypassed, and in wound healing and regeneration, where the process is reversed to allow renewed proliferation. Because the genetic networks that orchestrate patterning, differentiation, and cell cycle control are conserved between Drosophila and mammals, the results obtained herein should be generally relevant to human development and disease.

Theme 5: Intestinal Stem Cell Homeostasis

Objectives: To define the mechanisms controling the growth and proliferation of Drosophila adult gut stem cells, and use these cells to test models of human colon cancer.

Overview: The recent discovery of proliferative stem cells in the gut of adult Drosophila has provided an opportunity to study intestinal stem cell biology in a genetically tractable system. We and other labs have characterized the development of this stem cell population from its larval progenitors, and assessed the roles of known signaling pathways and cell cycle control genes in stem cell expansion. We find that Ras/MAPK signaling is a critical regulator of gut stem cell expansion during larval development, as well as during gut self-renewal in adults. Gut stem cell proliferation is also regulated by the Ack1 non-receptor tyrosine kinase mentioned above, by the JAK/STAT pathway, and by Cyclin E and the Cyclin E-specific inhibitor, P27/dacapo. Future studies will aim to profile gene expression patterns in the adult gut stem cells to determine the factors that allow their infinite renewal, and to further define the signals that regulate their growth and proliferation. Forward and reverse genetic screens will be undertaken to define genes that, like Ack1, deregulate stem cell expansion and gut hyperplasia. The functional homology between mammalian and insect gut homeostasis will be assessed, and novel genes found to regulate gut stem cell proliferation in Drosophila will be tested for similar roles in mammals.

Potential Impact: This project will develop a system for genetic studies of gut stem cell biology, and may identify novel genes important in stem cell regulation. After validation, the human orthologs of such genes may be useful targets for diagnosing and treating colon and other stem cell-based cancers.

Keywords

COS Keywords:

Cell Cycle, Genetics.

Languages

(Reading, Writing, Speaking)

German: (Basic, None, Basic)

Honors and Awards

1995-2000, Rita Allen Scholar, Rita Allen Foundation
1990-1999, Lucille P. Markey Scholar, Lucille P. Markey Charitable Trust
1988-1990, American Cancer Society Postdoctoral Fellowship, American Cancer Society
1988, Larry Sandler Memorial Award, National Drosophila Research Conference

Publications

  • Grewal SS, Evans JR, Edgar BA (Dec 2007) Drosophila TIF-IA is required for ribosome synthesis and cell growth and is regulated by the TOR pathway., The Journal of cell biology, 179 (6), 1105-13 Abstract
  • Buttitta LA, Edgar BA (Dec 2007) Mechanisms controlling cell cycle exit upon terminal differentiation., Current opinion in cell biology, 19 (6), 697-704 Abstract
  • Buttitta LA, Edgar BA (Nov 2007) How size is controlled: from Hippos to Yorkies., Nature cell biology, 9 (11), 1225-7 Abstract
  • O'Keefe DD, Prober DA, Moyle PS, Rickoll WL, Edgar BA (Nov 2007) Egfr/Ras signaling regulates DE-cadherin/Shotgun localization to control vein morphogenesis in the Drosophila wing., Developmental biology, 311 (1), 25-39 Abstract
  • Saucedo, L., Edgar, B. (2007) Filling out the Hippo pathway, Nature Reviews Molecular Cell Biology, 8 (8), 613-621
  • Oron, E., Tuller, T., Li, L., Rozovsky, N., Yekutieli, D., Rencus-Lazar, S., Segal, D., Chor, B., Edgar, B.A., Chamovitz, D. (2007) Genomic analysis of COP9 signalosome function in Drosophila melanogaster reveals a role in temporal regulation of gene expression, Molecular Systems Biology, 3, 108
  • Buttitta, L.A., Katzaroff, A.J., Perez, C.L., de la Cruz, A., Edgar, B.A. (2007) A Double-Assurance Mechanism Controls Cell Cycle Exit upon Terminal Differentiation in Drosophila, Developmental Cell, 12 (4), 631-643
  • Hall, D.J., Grewal, S.S., de la Cruz, A., Edgar, B. (2007) Rheb-TOR signaling promotes protein synthesis, but not glucose or amino acid import, in Drosophila, BMC Biology, 5 (10)
  • Edgar, B. (2006) How files get their size: genetics meets physiology, Nature Reviews Genetics, 7 (12), 907
  • Datar, S.A., Galloni, M., de la Cruz, A., Marti, M., Edgar, B.A., Frei, C. (2006) Mammalian Cyclin D1/Cdk4 complexes induce cell growth in Drosophila, Cell Cycle, 5, 647-652
  • Edgar, B.A. (2006) From Cell structure to transcription: Hippo forges a new path, Cell, 124, 267-273
  • Loo LW, Secombe J, Little JT, Carlos LS, Yost C, Cheng PF, Flynn EM, Edgar BA, Eisenman RN (Aug 2005) The transcriptional repressor dMnt is a regulator of growth in Drosophila melanogaster., Molecular and Cellular Biology, 25 (16), 7078-91 Abstract
  • Grewal SS, Li L, Orian A, Eisenman RN, Edgar BA (Mar 2005) Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development., Nature Cell Biology, 7 (3), 295-302 Abstract
  • Frei C, Galloni M, Hafen E, Edgar BA (Feb 2005) The Drosophila mitochondrial ribosomal protein mRpL12 is required for Cyclin D/Cdk4-driven growth., The Embo Journal, 24 (3), 623-34 Abstract
  • Emmerich J, Meyer CA, de la Cruz AF, Edgar BA, Lehner CF (Oct 2004) Cyclin D does not provide essential Cdk4-independent functions in Drosophila., Genetics, 168 (2), 867-75 Abstract
  • Pierce SB, Yost C, Britton JS, Loo LW, Flynn EM, Edgar BA, Eisenman RN, dMyc is required for larval growth and endoreplication in Drosophila, Development (cambridge, England), 131(10), 2317-27, May 2004 Abstract
  • Reis T, Edgar BA, Negative regulation of dE2F1 by cyclin-dependent kinases controls cell cycle timing, Cell, 117(2), 253-64, Apr 2004 Abstract
  • Frei C, Edgar BA, Drosophila cyclin D/Cdk4 requires Hif-1 prolyl hydroxylase to drive cell growth, Developmental Cell, 6(2), 241-51, Feb 2004 Abstract
  • Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA, Rheb promotes cell growth as a component of the insulin/TOR signalling network, Nature Cell Biology, 5(6), 566-71, Jun 2003 Abstract
  • Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D, Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins, Nature Cell Biology, 5(6), 578-81, Jun 2003 Abstract
  • Orian A, van Steensel B, Delrow J, Bussemaker HJ, Li L, Sawado T, Williams E, Loo LW, Cowley SM, Yost C, Pierce S, Edgar BA, Parkhurst SM, Eisenman RN, Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network, Genes & Development, 17(9), 1101-14, May 2003 Abstract
  • Prober DA, Edgar BA, Interactions between Ras1, dMyc, and dPI3K signaling in the developing Drosophila wing, Genes and Development, 16(17), 2286-99, September 2002 Abstract
  • Britton, J.S., Lockwood, W.B., Cohen, S.M., and Edgar, B.A., Drosophila's Insulin/PI3-Kinase Pathway Coordinates Cellular Metabolism with Nutritional Conditions, Developmental Cell, 2(2), 239-49, February 2002
  • Martín-Castellanos, C. and Edgar, B.A., A characterization of the effects of Dpp signaling on cell growth and proliferation in the Drosophila wing, Development, 129(4), 1003-1013, February 2002
  • Frank D.J., Edgar B.A., Roth M.B., The Drosophila melanogaster gene brain tumor negatively regulates cell growth and ribosomal RNA synthesis, Development, 129(2), 399-407, January 2002
  • Prober, D., Britton, J., de la Cruz, A.F., Johnston, J.A., Lehman, D., Martin-Castellanos, C. (2001) Pattern- and growth-linked cell cycles in Drosophila development In Edgar, B.A. (eds), The Cell Cycle and Development, 1st Edition, John Wiley and Sons, 3-18 pages, ISBN=0471496626 (bookchapter)
  • Edgar BA, Orr-Weaver TL, Endoreplication cell cycles: more for less, Cell, 105(3), 297-306, 2001 Abstract
  • Prober DA, Edgar BA, Growth regulation by oncogenes--new insights from model organisms, Current Opinion in Genetics and Development, 11(1), 19-26, February 2001 Abstract
  • Datar, S.A., Jacobs, H.W., de la Cruz, A.F., Lehner, C.F., Edgar, B.A. (2000) The Drosophila Cyclin D-Cdk4 complex promotes cellular growth, EMBO Journal, 19 (17), 4543
  • Meyer, C.A., Jacobs, H.W., Datar, S.A., Du, W., Edgar, B.A., Lehner, C.F. (2000) Drosophila Cdk4 is required for normal growth and is dispensable for cell cycle progression, EMBO Journal, 19 (17), 4533-4542
  • Prober DA, Edgar BA, Ras1 promotes cellular growth in the Drosophila wing, Cell, 100(4), 435-46, February 2000 Abstract
  • Edgar, BA, From small flies come big discoveries about size control, Nature Cell Biology, 1(8), E191-E193, December 1999
  • Johnston LA, Prober DA, Edgar BA, Eisenman RN, Gallant P, Drosophila myc regulates cellular growth during development, Cell, 98(6), 779-90, September 1999 Abstract
  • Migeon JC, Garfinkel MS, Edgar BA, Cloning and characterization of peter pan, a novel Drosophila gene required for larval growth, Molecular Biology of the Cell, 10(6), 1733-44, June 1999 Abstract
  • Galloni M, Edgar BA, Cell-autonomous and non-autonomous growth-defective mutants of Drosophila melanogaster, Development, 126(11), 2365-75, June 1999 Abstract
  • Lehman DA, Patterson B, Johnston LA, Balzer T, Britton JS, Saint R, Edgar BA, Cis-regulatory elements of the mitotic regulator, string/Cdc25, Development, 126(9), 1793-803, May 1999 Abstract
  • Neufeld TP, Edgar BA, Connections between growth and the cell cycle, Current Opinion in Cell Biology, 10(6), 784-90, December 1998 Abstract
  • Johnston LA, Edgar BA, Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing, Nature, 394(6688), 82-4, July 1998 Abstract
  • Neufeld TP, de la Cruz AF, Johnston LA, Edgar BA, Coordination of growth and cell division in the Drosophila wing, Cell, 93(7), 1183-93, June 1998 Abstract
  • Britton JS, Edgar BA, Environmental control of the cell cycle in Drosophila: nutrition activates mitotic and endoreplicative cells by distinct mechanisms, Development, 125(11), 2149-58, June 1998 Abstract
  • Edgar BA, Lehner CF, Developmental control of cell cycle regulators: a fly's perspective, Science, 274(5293), 1646-52, December 1996 Abstract
  • Edgar BA, Datar SA, Zygotic degradation of two maternal Cdc25 mRNAs terminates Drosophila's early cell cycle program, Genes and Development, 10(15), 1966-77, August 1996 Abstract
  • Edgar B, Diversification of cell cycle controls in developing embryos., Curr Opin Cell Biol, 7(6), 815-24, December 1995 Abstract
  • Campbell SD, Sprenger F, Edgar BA, O'Farrell PH (Oct 1995) Drosophila Wee1 kinase rescues fission yeast from mitotic catastrophe and phosphorylates Drosophila Cdc2 in vitro., Molecular Biology of the Cell, 6 (10), 1333-47 Abstract
  • Edgar BA, Lehman DA, O'Farrell PH, Transcriptional regulation of string (cdc25): a link between developmental programming and the cell cycle, Development, 120(11), 3131-43, November 1994 Abstract
  • Edgar, B.A. (1994) Cell-cycle control in developmental context, Current Biology, 4 (6), 522-524
  • Edwards KA, Montague RA, Shepard S, Edgar BA, Erikson RL, Kiehart DP (May 1994) Identification of Drosophila cytoskeletal proteins by induction of abnormal cell shape in fission yeast., Proceedings of the National Academy of Sciences of the United States of America., 91 (10), 4589-93 Abstract
  • Edgar BA, Sprenger F, Duronio RJ, Leopold P, O'Farrell PH, Distinct molecular mechanism regulate cell cycle timing at successive stages of Drosophila embryogenesis, Genes and Development, 8(4), 440-52, February 1994 Abstract
  • Schubiger, G., Edgar, B.A. (1994) Using Inhibitors to Study Embryogenesis, Methods in Cell Biology, 44, 697-713
  • Foe, V.E., Odell, G.M. (1993) Mitosis and Morphogenesis in the Drosophila Embryo: Point and Counterpoint In Edgar, B.A. (eds), The Development of Drosophila melanogaster, Plainview, NY, Cold Spring Harbor Laboratory Press, 149-300 pages, Submitted, ISBN=0879694238 (bookchapter)
  • Edgar BA, O'Farrell PH, The three postblastoderm cell cycles of Drosophila embryogenesis are regulated in G2 by string, Cell, 62(3), 469-80, August 1990 Abstract
  • O'Farrell PH, Edgar BA, Lakich D, Lehner CF (Nov 1989) Directing cell division during development., Science, 246 (4930), 635-40 Abstract
  • Edgar BA, O'Farrell PH, Genetic control of cell division patterns in the Drosophila embryo, Cell, 57(1), 177-87, April 1989 Abstract
  • Weir MP, Edgar BA, Kornberg T, Schubiger G (Sep 1988) Spatial regulation of engrailed expression in the Drosophila embryo., Genes & Development, 2 (9), 1194-203 Abstract
  • Edgar, B.A., Odell, G.M., Schubiger, G. (1987) Cytoarchitecture and the patterning of fushi tarazu expression in the Drosophila blastoderm., Genes & Development, 1 (10), 1226-1237
  • Shinedling S, Singer BS, Gayle M, Pribnow D, Jarvis E, Edgar B, Gold L (Jun 1987) Sequences and studies of bacteriophage T4 rII mutants., Journal of Molecular Biology, 195 (3), 471-80 Abstract
  • Edgar BA, Weir MP, Schubiger G, Kornberg T (Dec 1986) Repression and turnover pattern fushi tarazu RNA in the early Drosophila embryo., Cell, 47 (5), 747-54 Abstract
  • Edgar BA, Schubiger G (Mar 1986) Parameters controlling transcriptional activation during early Drosophila development., Cell, 44 (6), 871-7 Abstract
  • Edgar BA, Kiehle CP, Schubiger G (Jan 1986) Cell cycle control by the nucleo-cytoplasmic ratio in early Drosophila development., Cell, 44 (2), 365-72 Abstract
  • Payvar F, DeFranco D, Firestone GL, Edgar B, Wrange O, Okret S, Gustafsson JA, Yamamoto KR (Dec 1983) Sequence-specific binding of glucocorticoid receptor to MTV DNA at sites within and upstream of the transcribed region., Cell, 35 (2 Pt 1), 381-92 Abstract

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