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    Andreas Bergmann PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentCancer Biology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB Suite 419
    Worcester MA 01605
    Phone508-856-6423
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCancer Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

        Overview 
        Narrative

        Genetic Control of Programmed Cell Death (Apoptosis) in Drosophila

        The long-term objective of our research is to gain a comprehensive understanding ofAndreasBergmann thegenetic control of apoptosis and cell proliferation, and their connection to human cancer. Apoptosis and cell proliferation are critical for normal development, homeostasis and aging. Inappropriate control is associated with various diseases including cancer and neurodegeneration. We are utilizing the fruit fly Drosophila melanogaster as a genetic model organism. Knowledge obtained in our studies will provide new insights for our understanding of these diseases.

        A tutorial in the lab will provide a detailed introduction into modern Drosophila techniques with emphasis on visualizing gene activity and cell death in wild-type and various mutant backgrounds, phenotypic analysis, generating transgenic flies and small scale genetic screens. In addition, students will gain experience in basic molecular biology and protein chemistry. The experiments will be aided by state-of-the-art facilities.

        Three major projects are under study in the lab.

        1. Genetic screening

        We have developed a novel genetic screening method to identify genes involved in cell death control and execution in Drosophila (Figure 1). However, unexpectedly, we also identified genes involved in growth control, signal transduction and tumor suppression. These interesting genes and their role in normal development are currently under intensive study in the lab.

        2. Discovery of non-autonomous tumor suppressor genes

        We have discovered a novel class of tumor suppressor genes. Normally, cells that lose tumor suppressor genes by genetic inactivation become highly proliferative and resistant to apoptosis, thus promoting tumor formation. However, in our studies, we identified genes which behave differently. If these genes are mutant, it is not the mutant cells which are overgrowing. Instead, the mutant cells influence the behavior of neighboring cells and promote their proliferation and increased apoptotic resistance, causing non-autonomous overgrowth. Thus, these genes qualify as non-autonomous tumor suppressors.

        How do non-autonomous tumor suppressor genes work? One class of non-autonomous mutants affects negative regulators of the Hedgehog (Hh) pathway such as patched or PKA, causing deregulated Hh signaling. This deregulated activity promotes non-autonomous proliferation as well as increased apoptosis resistance through up-regulation of Diap1, a potent inhibitor of apoptosis (Figure 2). The non-autonomous control of proliferation and apoptosis by Hh signaling may be needed to generate a supportive micro-environment for tumorigenesis.

        3. Apoptosis-induced compensatory proliferation (CP) and its implications for cancer

        Before they die, apoptotic cells can secrete cytokines. These cytokines stimulate proliferation of neighboring cells, a process referred to as apoptosis-induced compensatory proliferation (CP). There are two distinct types of apoptosis-induced compensatory proliferation. The first one is triggered when massive apoptosis is induced in proliferation-competent tissue (Figure 3). In extreme cases, this form of CP causes overgrowth which may be relevant for cancer (Figure 4). The second type of CP occurs when apoptosis is induced in post-mitotic tissue (Figure 5).

        Understanding the molecular mechanisms of CP is important for cancer research for three reasons. First, apoptosis-induced proliferation resembles inflammation-induced cancer where inflammatory cells secrete cytokines promoting the growth of cancer cells. Second, therapeutic treatment of tumors often seeks to induce apoptosis of cancer cells. However, this may be counter-productive as apoptotic cells can induce proliferation of adjacent cells. In extreme cases, we observe overgrowth of apoptotic tissue. Third, a very important question in cancer research is how transformed cells start proliferating. This is not a trivial question. Cells in a differentiated tissue have exited the cell cycle and rest in a quiescent state. The exact molecular mechanisms by which transformed cells re-enter the cell cycle are largely unknown. The second type of CP may provide answers to this question. When we induce apoptosis in the Drosophila retina which is composed of postmitotic neurons, cone and pigment cells, the neurons produce mitogens which stimulate other cells to re-enter the cell cycle (Figure 5). The characteristics of this cell cycle re-entry are similar to mammalian cells stimulated to re-enter the cell cycle.

        Thus, these examples illustrate the importance of CP in for cancer. In genetic screens, we have identified several genes involved in CP. We are analyzing these genes to understand the mechanism of CP and their potential role in cancer.

        Significance

        Initially, the primary focus of research in the laboratory centered on apoptosis. However, over the years it became clear that in the context of a multi-cellular organism such as Drosophila, apoptosis is intimately linked to cell proliferation and tumor suppression. The discovery of apoptosis-induced compensatory proliferation is an instructive example. Although the cells are dying, they are able to produce cytokines that stimulate proliferation. In extreme cases, this can cause overgrowth. Because induction of apoptosis in tumor cells is a preferred strategy in the clinic, it is important to understand the mechanism of apoptosis-induced proliferation. Likewise, tumor cells need a supportive cellular micro-environment for tumorigenesis. Non-autonomous tumor suppressor genes may generate such a supportive environment. Therefore, it is important to understand the mechanism of action of these genes. The projects in the laboratory are aimed at these questions.

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        Post Docs

        Please contact the Human Resources at UMass for openings in Dr. Bergmann's lab.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Woodfield SE, Graves HK, Hernandez JA, Bergmann A. De-Regulation of JNK and JAK/STAT Signaling in ESCRT-II Mutant Tissues Cooperatively Contributes to Neoplastic Tumorigenesis. PLoS One. 2013; 8(2):e56021.
          View in: PubMed
        2. Christiansen AE, Ding T, Fan Y, Graves HK, Herz HM, Lindblad JL, Bergmann A. Non-cell autonomous control of apoptosis by ligand-independent Hedgehog signaling in Drosophila. Cell Death Differ. 2013 Feb; 20(2):302-11.
          View in: PubMed
        3. Mollereau B, Perez-Garijo A, Bergmann A, Miura M, Gerlitz O, Ryoo HD, Steller H, Morata G. Compensatory proliferation and apoptosis-induced proliferation: a need for clarification. Cell Death Differ. 2013 Jan; 20(1):181.
          View in: PubMed
        4. Graves HK, Woodfield SE, Yang CC, Halder G, Bergmann A. Notch signaling activates yorkie non-cell autonomously in Drosophila. PLoS One. 2012; 7(6):e37615.
          View in: PubMed
        5. Christiansen AE, Ding T, Bergmann A. Ligand-independent activation of the Hedgehog pathway displays non-cell autonomous proliferation during eye development in Drosophila. Mech Dev. 2012 Jul; 129(5-8):98-108.
          View in: PubMed
        6. Lee TV, Fan Y, Wang S, Srivastava M, Broemer M, Meier P, Bergmann A. Drosophila IAP1-mediated ubiquitylation controls activation of the initiator caspase DRONC independent of protein degradation. PLoS Genet. 2011 Sep; 7(9):e1002261.
          View in: PubMed
        7. Anderson AE, Karandikar UC, Pepple KL, Chen Z, Bergmann A, Mardon G. The enhancer of trithorax and polycomb gene Caf1/p55 is essential for cell survival and patterning in Drosophila development. Development. 2011 May; 138(10):1957-66.
          View in: PubMed
        8. Jankowska EA, Filippatos GS, von Haehling S, Papassotiriou J, Morgenthaler NG, Cicoira M, Schefold JC, Rozentryt P, Ponikowska B, Doehner W, Banasiak W, Hartmann O, Struck J, Bergmann A, Anker SD, Ponikowski P. Identification of chronic heart failure patients with a high 12-month mortality risk using biomarkers including plasma C-terminal pro-endothelin-1. PLoS One. 2011; 6(1):e14506.
          View in: PubMed
        9. Bergmann A, Steller H. Apoptosis, stem cells, and tissue regeneration. Sci Signal. 2010; 3(145):re8.
          View in: PubMed
        10. Wang Y, Chen Z, Bergmann A. Regulation of EGFR and Notch signaling by distinct isoforms of D-cbl during Drosophila development. Dev Biol. 2010 Jun 1; 342(1):1-10.
          View in: PubMed
        11. Herz HM, Madden LD, Chen Z, Bolduc C, Buff E, Gupta R, Davuluri R, Shilatifard A, Hariharan IK, Bergmann A. The H3K27me3 demethylase dUTX is a suppressor of Notch- and Rb-dependent tumors in Drosophila. Mol Cell Biol. 2010 May; 30(10):2485-97.
          View in: PubMed
        12. Bergmann A. The role of ubiquitylation for the control of cell death in Drosophila. Cell Death Differ. 2010 Jan; 17(1):61-7.
          View in: PubMed
        13. Fan Y, Bergmann A. The cleaved-Caspase-3 antibody is a marker of Caspase-9-like DRONC activity in Drosophila. Cell Death Differ. 2010 Mar; 17(3):534-9.
          View in: PubMed
        14. Fan Y, Lee TV, Xu D, Chen Z, Lamblin AF, Steller H, Bergmann A. Dual roles of Drosophila p53 in cell death and cell differentiation. Cell Death Differ. 2010 Jun; 17(6):912-21.
          View in: PubMed
        15. Allton K, Jain AK, Herz HM, Tsai WW, Jung SY, Qin J, Bergmann A, Johnson RL, Barton MC. Trim24 targets endogenous p53 for degradation. Proc Natl Acad Sci U S A. 2009 Jul 14; 106(28):11612-6.
          View in: PubMed
        16. Herz HM, Bergmann A. Genetic analysis of ESCRT function in Drosophila: a tumour model for human Tsg101. Biochem Soc Trans. 2009 Feb; 37(Pt 1):204-7.
          View in: PubMed
        17. Herz HM, Woodfield SE, Chen Z, Bolduc C, Bergmann A. Common and distinct genetic properties of ESCRT-II components in Drosophila. PLoS One. 2009; 4(1):e4165.
          View in: PubMed
        18. Xu D, Woodfield SE, Lee TV, Fan Y, Antonio C, Bergmann A. Genetic control of programmed cell death (apoptosis) in Drosophila. Fly (Austin). 2009 Jan-Mar; 3(1):78-90.
          View in: PubMed
        19. Ditzel M, Broemer M, Tenev T, Bolduc C, Lee TV, Rigbolt KT, Elliott R, Zvelebil M, Blagoev B, Bergmann A, Meier P. Inactivation of effector caspases through nondegradative polyubiquitylation. Mol Cell. 2008 Nov 21; 32(4):540-53.
          View in: PubMed
        20. Fan Y, Bergmann A. Apoptosis-induced compensatory proliferation. The Cell is dead. Long live the Cell! Trends Cell Biol. 2008 Oct; 18(10):467-73.
          View in: PubMed
        21. Fan Y, Bergmann A. Distinct mechanisms of apoptosis-induced compensatory proliferation in proliferating and differentiating tissues in the Drosophila eye. Dev Cell. 2008 Mar; 14(3):399-410.
          View in: PubMed
        22. Wang Y, Werz C, Xu D, Chen Z, Li Y, Hafen E, Bergmann A. Drosophila cbl is essential for control of cell death and cell differentiation during eye development. PLoS One. 2008; 3(1):e1447.
          View in: PubMed
        23. Bergmann A. Autophagy and cell death: no longer at odds. Cell. 2007 Dec 14; 131(6):1032-4.
          View in: PubMed
        24. Lee TV, Ding T, Chen Z, Rajendran V, Scherr H, Lackey M, Bolduc C, Bergmann A. The E1 ubiquitin-activating enzyme Uba1 in Drosophila controls apoptosis autonomously and tissue growth non-autonomously. Development. 2008 Jan; 135(1):43-52.
          View in: PubMed
        25. Mendes CS, Arama E, Brown S, Scherr H, Srivastava M, Bergmann A, Steller H, Mollereau B. Cytochrome c-d regulates developmental apoptosis in the Drosophila retina. EMBO Rep. 2006 Sep; 7(9):933-9.
          View in: PubMed
        26. Bergmann A. IKK epsilon signaling: not just NF-kappaB. Curr Biol. 2006 Aug 8; 16(15):R588-90.
          View in: PubMed
        27. Xu D, Wang Y, Willecke R, Chen Z, Ding T, Bergmann A. The effector caspases drICE and dcp-1 have partially overlapping functions in the apoptotic pathway in Drosophila. Cell Death Differ. 2006 Oct; 13(10):1697-706.
          View in: PubMed
        28. Srivastava M, Scherr H, Lackey M, Xu D, Chen Z, Lu J, Bergmann A. ARK, the Apaf-1 related killer in Drosophila, requires diverse domains for its apoptotic activity. Cell Death Differ. 2007 Jan; 14(1):92-102.
          View in: PubMed
        29. Herz HM, Chen Z, Scherr H, Lackey M, Bolduc C, Bergmann A. vps25 mosaics display non-autonomous cell survival and overgrowth, and autonomous apoptosis. Development. 2006 May; 133(10):1871-80.
          View in: PubMed
        30. Arama E, Bader M, Srivastava M, Bergmann A, Steller H. The two Drosophila cytochrome C proteins can function in both respiration and caspase activation. EMBO J. 2006 Jan 11; 25(1):232-43.
          View in: PubMed
        31. Werz C, Lee TV, Lee PL, Lackey M, Bolduc C, Stein DS, Bergmann A. 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; 132(24):5343-52.
          View in: PubMed
        32. Cashio P, Lee TV, Bergmann A. Genetic control of programmed cell death in Drosophila melanogaster. Semin Cell Dev Biol. 2005 Apr; 16(2):225-35.
          View in: PubMed
        33. Xu D, Li Y, Arcaro M, Lackey M, Bergmann A. The CARD-carrying caspase Dronc is essential for most, but not all, developmental cell death in Drosophila. Development. 2005 May; 132(9):2125-34.
          View in: PubMed
        34. Bergmann A, Yang AY, Srivastava M. Regulators of IAP function: coming to grips with the grim reaper. Curr Opin Cell Biol. 2003 Dec; 15(6):717-24.
          View in: PubMed
        35. Bergmann A, Lane ME. HIDden targets of microRNAs for growth control. Trends Biochem Sci. 2003 Sep; 28(9):461-3.
          View in: PubMed
        36. Sathyanarayana P, Barthwal MK, Lane ME, Acevedo SF, Skoulakis EM, Bergmann A, Rana A. Drosophila mixed lineage kinase/slipper, a missing biochemical link in Drosophila JNK signaling. Biochim Biophys Acta. 2003 Apr 7; 1640(1):77-84.
          View in: PubMed
        37. Sathyanarayana P, Barthwal MK, Kundu CN, Lane ME, Bergmann A, Tzivion G, Rana A. Activation of the Drosophila MLK by ceramide reveals TNF-alpha and ceramide as agonists of mammalian MLK3. Mol Cell. 2002 Dec; 10(6):1527-33.
          View in: PubMed
        38. Bergmann A. Survival signaling goes BAD. Dev Cell. 2002 Nov; 3(5):607-8.
          View in: PubMed
        39. Ryoo HD, Bergmann A, Gonen H, Ciechanover A, Steller H. Regulation of Drosophila IAP1 degradation and apoptosis by reaper and ubcD1. Nat Cell Biol. 2002 Jun; 4(6):432-8.
          View in: PubMed
        40. Bergmann A, Tugentman M, Shilo BZ, Steller H. Regulation of cell number by MAPK-dependent control of apoptosis: a mechanism for trophic survival signaling. Dev Cell. 2002 Feb; 2(2):159-70.
          View in: PubMed
        41. Towb P, Bergmann A, Wasserman SA. The protein kinase Pelle mediates feedback regulation in the Drosophila Toll signaling pathway. Development. 2001 Dec; 128(23):4729-36.
          View in: PubMed
        42. Kim J, Bergmann A, Wehri E, Lu X, Stubbs L. Imprinting and evolution of two Kruppel-type zinc-finger genes, ZIM3 and ZNF264, located in the PEG3/USP29 imprinted domain. Genomics. 2001 Sep; 77(1-2):91-8.
          View in: PubMed
        43. Bergmann A, Agapite J, Steller H. Mechanisms and control of programmed cell death in invertebrates. Oncogene. 1998 Dec 24; 17(25):3215-23.
          View in: PubMed
        44. Bergmann A, Agapite J, McCall K, Steller H. The Drosophila gene hid is a direct molecular target of Ras-dependent survival signaling. Cell. 1998 Oct 30; 95(3):331-41.
          View in: PubMed
        45. Bergmann A, Stein D, Geisler R, Hagenmaier S, Schmid B, Fernandez N, Schnell B, Nüsslein-Volhard C. A gradient of cytoplasmic Cactus degradation establishes the nuclear localization gradient of the dorsal morphogen in Drosophila. Mech Dev. 1996 Nov; 60(1):109-23.
          View in: PubMed
        46. Grosshans J, Bergmann A, Haffter P, Nüsslein-Volhard C. Activation of the kinase Pelle by Tube in the dorsoventral signal transduction pathway of Drosophila embryo. Nature. 1994 Dec 8; 372(6506):563-6.
          View in: PubMed
        47. Geisler R, Bergmann A, Hiromi Y, Nüsslein-Volhard C. cactus, a gene involved in dorsoventral pattern formation of Drosophila, is related to the I kappa B gene family of vertebrates. Cell. 1992 Nov 13; 71(4):613-21.
          View in: PubMed
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