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When the control is lacking—the role of tumour suppressor genes in cancer development

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Abstract

The potential to genetically dissect tumorigenesis provides the major reason to study this process in the fruit flyDrosophila. Over the last 30 years genetic analysis has identified some 55 genes in which recessive mutations cause the appearance of specific tumours during development in tissues such as the imaginal discs, the brain hemispheres, the hematopoietic organs or the gonads, Since the normal allele acts dominantly over the mutated allele, these genes are designated as tumour suppressor genes. The estimate of the number of genes that can be mutated to tumour formation may be, however, much higher ranging between I00 to 200. The challenge before this field is how best to identify these genes and elucidate their function. Current molecular procedures, such as mutagenesis mediated by P-element transposon, provide new ways for tagging any gene of interest inDrosophila and thus for cloning it rapidly. Function of the gene product can be inferred by comparing its amino acid sequence with sequences of proteins with known function or can be determined by histochemical and biochemical investigations.

Progress in the understanding of tumour suppression inDrosophila is most advanced in the case of genes regulating cell growth in imaginal discs. The imaginal discs are small groups of cells displaying a strong apical-basal polarity and form folded sacs of epithelia which grow throughout the larval life and give rise to the adult tegument during metamorphosis. Tumour suppressor genes regulating cell growth of imaginal discs, such as thelethal(2)giant larvae (l(2)g1),lethal(1)discs large-1 andexpanded genes, were found to encode proteins localized in domains of cell to cell contact on the plasma membrane and were thus thought to maintain cell adhesion. However, recent studies of l(2)gl have revealed that the l(2)gl protein is a component of the normal cytoskeleton which can participates to the cytoskeletal matrix underlaying the plasma membrane. These findings indicate that the changes in cell shape and the loss of apical-basal polarity in imaginal disc cells result primarily from alterations in the cytoskeleton structure. Furthermore the neoplastic growth of the mutated cells may be caused by the disorganization of an intracellular communication system that ultimately controls cell proliferation and/or cell differentiation.

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References

  • Becker H J 1976 Mitotic recombination; inThe genetics and biology of Drosophila (eds) M Ashburner and E Novitski (London: Academic Press) Vol. I C, pp 1019–1087

    Google Scholar 

  • Boedigheimer M and Laughon A 1993expanded: a gene involved in the control of cell proliferation in imaginal discs;Development 118 1291–1301

    PubMed  CAS  Google Scholar 

  • Bridges C B and Brehme K F 1944 The mutationof Drosophila melanogaster (Carnegie Institute of Washington) Publication No. 522

  • Bryant P 1 1987 Experimental and genetic analysis of growth and cell proliferation inDrosophila imaginal discs; inGenetic regulation of development (ed.) W F Loomis (New York: Alan R Liss) pp 339–372

    Google Scholar 

  • Bryant P J and Woods D F 1992 A major palmitoylated membrane protein of human erythrocytes shows homology to yeast guanylate kinase and to the product of aDrosophila tumour gene;Cell 68 621–622

    Article  PubMed  CAS  Google Scholar 

  • Campos-Ortega J A and Hartenstein V 1985The embryonic development of Drosophila melanogaster (Berlin: Springer Verlag)

    Google Scholar 

  • Cawthon R M, Weis R, Xu G, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O’Connell P and White R 1990 A major segment of the neurofibromatosis type 1 gene: cDNA sequence, gcnomic structure, and point mutations;Cell 62 193–201

    Article  PubMed  CAS  Google Scholar 

  • Chen M S, Obar R A, Schroeder A. C, Austin T W, Poodry A. A, Wadsworth S C and Vallee R B 1991 Multiple forms of dynamin are encoded byshibire, aDrosophila gene involved in endocytosis;Nature (London) 351 583–586

    Article  CAS  Google Scholar 

  • Cho K-0, Hunt A. A and Kennedy M B 1992 The rat brain postsynaptic density fraction contains a homolog of theDrosophila discs-large tumor suppressor protein;Neuron 9 929–942

    Article  PubMed  CAS  Google Scholar 

  • Dalrymple M A, Petersen-Bjorn S, Friesen J D and Beggs J D 1989 The product of thePRP4 gene ofS. cerevisiae shows homology to 13-subunits of G Proteins;Cell 58 811–812

    Article  PubMed  CAS  Google Scholar 

  • Diaz-Benjumea F J and Garcia-Bellido A 1990 Genetic analysis of the wing vein pattern of Drosophila;Roux’s Arch. Dev, Biol,198 336–354

    Article  Google Scholar 

  • Fearon E R, Cho K R, Nigro J M, Kern S E, Simons J W, Ruppert J M, Hamilton S R, Preisinger A C, Thomas G, Kinzler K W and Vogelstein B 1990 Identification of a chromosome I8q gene that is altered in colorectal cancers;Science 247 49–56

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Bellido A and deCelis J F 1992 Developmental Genetics of the venation pattern ofDrosophila;Annu. Rev. Genet. 26 275–302

    Article  Google Scholar 

  • Garen A Kauvar L and Lepesant J A 1977 Roles of ecdysone inDrosophila development;Proc. Natl. Acad. Sci. USA 74 5099–5102

    Article  PubMed  CAS  Google Scholar 

  • Garrel J and Campuzano S 1991 The helix-loop-helix domain a common motif for btistles, muscles and sex;Bioessays 10 493–498

    Article  Google Scholar 

  • Gateff E 1978 Malignant neoplasms of genetic origin in the fruit flyDrosophila melanogaster;Science 200 1446-I459

    Article  Google Scholar 

  • Gateff E and Mechler B M 1989 Tumor-suppressor genes ofDrosophila melanogaster;CRC Crit. Rev. Oncogenesis 1 221–245

    CAS  Google Scholar 

  • Gateff E and Schneiderman H A 1967 Developmental studies of a new mutation ofDrosophila melanogaster: lethal malignant brain tumor l(2)gl4;Am. Zoo!. 7 760

    Google Scholar 

  • Gateff E and Schneiderman H A 1969 Neoplasms in mutant and cultured wild-type tissues ofDrosophila;Natl. Cancer Inst. Monogr. 31 365–397

    PubMed  CAS  Google Scholar 

  • Gateff E and Schneiderman H A 1974 Developmental capacities of benign and malignant neoplasms ofDrosophila;Wilhelm Roux’ Arch. Entwicklungsmech. Org. 176 23–65

    Article  Google Scholar 

  • Geiger B 1983 Membrane-cytoskeleton interaction;Biophys. Acta 737 305–341

    CAS  Google Scholar 

  • Glorr H 1943 Entwicklungsphysiologische Untersuchung an den Gonaden einer Letalrasse (1g1) von Drosophilamelanogaster;Rev. Suisse Zool. 50 339–394

    Google Scholar 

  • Golic K G 1991 Site-specific recombination between homologous chromosomes inDrosophila;Science 252 958–961

    Article  PubMed  CAS  Google Scholar 

  • Golubovsky M D 1978 The “lethal giant larvae”-the most frequent second chromosome lethal in natural populations ofD. melanogaster;Drosophila In’: Serv. 53 179

    Google Scholar 

  • Golubovsky M D 1980 Mutational process and microevolution;Genetica 52/53 139–149

    Article  Google Scholar 

  • Graziani G, Ron R, Eva A and Srivastava S 1989 The human abl-proto-oncogene product is a cytoplasmic phosphoprotein which is associated with the cytoskeletal matrix;Oncogene 4 823–829

    PubMed  CAS  Google Scholar 

  • Green M M and Sheperd SHY 1979 Genetic instability inDrosophila melanogaster: the induction of specific chromosome 2 deletions by MR element;Genetics 92 823–832

    PubMed  CAS  Google Scholar 

  • Hadron E 1937 An accelerating effect of normal ‘ring glands’ on puparium formation in lethal larvae ofDrosophila melanogaster;Proc. Natl. Acad. Sci. USA 23 478–484

    Article  Google Scholar 

  • Hadron E 1961Developmental genetics and lethal factors (London: Methuen)

    Google Scholar 

  • Hadorn E and Gloor H 1942 Die Auswirkung eines Letalfaktors(lgl) beiDrosophila melanogaster aus Wachsturn and Differenzierung der Gonaden;Rev. Suisse Zool. 49 228–236

    Google Scholar 

  • Hankins G R 1990Analysis of a Drosophila neuroblastoma gene, PhD Dissertation, University of Virginia, Charlottesville

    Google Scholar 

  • Hanratty W P and Ryerse J S 1981 A genetic melanotic neoplasm ofDrosophila melanogaster;Dev. Biol. 83 238–249

    Article  PubMed  CAS  Google Scholar 

  • Harris H, Miller 0 J, Klein G, Worst P and Tachibana T 1969 Suppression of malignancy by cell fusion;Nature (London) 223 363–368

    Article  CAS  Google Scholar 

  • Jacob L, Upper M, Metzroth B, Phannavong B and Mechler B M 1987 Structure of the l(2)gl gene ofDrosophila and delimitation of its tumor suppressor domain;Cell 50 215–225

    Article  PubMed  CAS  Google Scholar 

  • Karlson P and Hauser G 1952 Ober die Wirkung des Puparisierungshormons bei der Wildform und der Mutantelgl vonDrosophila;Z. Naturjorsch, 7b 80–83

    Google Scholar 

  • Kmmbt C, Muller S, Lutzelschwab R, Rossa R, Totzke F and Schmidt 0 1989The Drosophila melanogaster l(2)gl gene encodes a protein homologous to the cadherin cell-adhesion molecular family;Dev. Biol. 133 425–436

    Article  Google Scholar 

  • Knudson G A 1971 Mutation and cancer: Statistical study of retinoblastoma;Proc. Natl. Acad. Sci. USA 68 820–823

    Article  PubMed  Google Scholar 

  • Knudson G A 1993 All in the (cancer) family;Nature Genet. 5 103–104

    Article  PubMed  CAS  Google Scholar 

  • Koonin E V, Woods D F and Bryant P J 1992 dlg-R proteins: modified guanylate kinases;Nature Genet. (in press)

  • Lewis E B 1945 The relation of repeats to position effect inDrosophila melanogaster;Genetics 36 137–166

    Google Scholar 

  • Lindsley D L and Zimm G G 1992The genuine of Drosophila melanogaster (San Diego: Academic Press)

    Google Scholar 

  • Liitzelschwab R, Klambt C, Rossa R and Schmidt O 1987 A protein product of theDrosophila recessive tumour gene l(2)giantgl, potentially has all adhesion properties;EMBO J. 6 1791–1797

    Google Scholar 

  • Lutzelschwab R, Muller G, Icier B, Schmidt O Furbass R and Mechler B 1986 Insertion mutation inactivates the expression of the recessive oncogene lethal(2)giantlarvae ofDrosophila melanogaster;Mot. Gen. Genet. 204 58–63

    Article  Google Scholar 

  • Mahoney P A, Weber U, Onofrechuck P, Biessmann H, Bryant P J and Goodman A. S 1991 Thefat tumor suppressor gene inDrosophila encodes a novel member of the cadherin gene family;Cell 67 853–868

    Article  PubMed  CAS  Google Scholar 

  • McCrea P D and Gumbiner B M 1991 Purification of a 92-kDa cytoplasmic protein tightly associated with the cell-cell adhesion molecule E-cadherin (Uvomorulin);Biol. Chem. 266 4514–4520

    CAS  Google Scholar 

  • McKeavin D M and Spradling A C 1990bag-of-marbles: aDrosophila gene required to initiate both male and female gametogenesis;Genes Derv. 4 2242–2251

    Article  Google Scholar 

  • Mechier B M 1984 Molecular cloning of the recessive oncogene lethal(2)giantlarvae ofDrosophila nielanogaster;Ear. J. Cell Biol,33 23

    Google Scholar 

  • Mechier B M 1991 The fruitflyDrosophila and the fishXiphophorus as model systems for cancer studies;Cancer Surv. 9 505–527

    Google Scholar 

  • Mechler B M, McGinnis W and Gehring W J 1985 Molecular cloning oflethal(2)giant larvae, a recessive oncogeneof Drosophila melanogasterr;EMBO.J. 4 1551–1557

    PubMed  CAS  Google Scholar 

  • Mechier B M and Strand D 1990 Tumor suppression inDrosophila; inTumor suppressor genes (ed.) G Klein (New York, Basel: Marcel Dekker) pp 123–144

    Google Scholar 

  • Mechler B, Strand D, Kalmes A, Merz R, Schmidt M and Torok I 1991Drosophila as a model system for molecular analysis of tumorigenesis;Environ. Health Persp. 93 63–71

    Article  CAS  Google Scholar 

  • Herz R, Schmidt M, Torok I, Protin U, Schuler G, Walther H P, Krieg F, Gross M, Strand D and Mechler B M 1990 Molecular action of the l(2)gl tumour suppressor gene ofDrosophila melanogaster;Environ. Health Persp. 88 163–167

    Article  Google Scholar 

  • Upper M, Schuler G and Mechier B M 1987 Hereditary suppression of lethal(2)giantlarvae malignant tumor development inDrosophila by gene transfer;Oncogene 1 9I-96

    Google Scholar 

  • Poodry A. A 1990shibire, neurogenic mutantof Drosophila;Dev. Biol. 138 464–472

    Article  PubMed  CAS  Google Scholar 

  • Preat T, Therond P, Lamour-Isnard C, Limbourg-Bouchon B, Tricoire H, Erk I, Mariol M-L and Busson D 1990 A putative serine/threonine protein kinase encoded by the segment-polarity gene fused ofDrosophila;Nature (London) 347, 87–89

    Article  CAS  Google Scholar 

  • Richards G P 1976 Thein vitro induction of puffing in salivary glands of the mutant l(2)gl ofDrosophila melanogaster by ecdysone;Roux’s Arch. Dev. Biol. 179 339–348

    Article  Google Scholar 

  • Schubiger M and Palka J 1987 Changing spatial patterns of DNA replication in the developing wing ofDrosophila;Dev. Biol. 123 I45-I53

    Article  Google Scholar 

  • Staniunas R, Mafune K, Lu M, Chen L and Steele G Jr 1990 Increased expression of ribosomal protein S6 in human colon cancer;Surg. Forum 41 457–459

    Google Scholar 

  • Steinbauer N R, Walsh R C and Kalfayan L J 1989 Sequence and structure of theDrosophila melanogaster ovarian tumor gene and generation of an antibody specific for the ovarian tumor protein;Mol, Cell. Biol. 9 57.26–57.32

    Google Scholar 

  • Stewart M J and DeneII R 1993 Mutations in the 5′ region of theDrosophila gene encoding ribosomal protein S6 are associated with tissue overgrowth;Mol. Cell. Biol. 13 2524–2535

    PubMed  CAS  Google Scholar 

  • Strand D, Raska 1 and Mechler B 1993 TheDrosophila l(2)gl tumour suppressor protein acts as an intracellular cytoskeletal protein associated to lateral cell junctions. (submitted)

  • Strand D, Torok 1, Kalmes A, Schmidt M, Merz R and Mechier B M 1991 Transcriptional and translational regulation of the expression of the l(2)gl tumor suppressor gene ofDrosophila melanogaster;in Advances in enzyme regulation (ed.) George Weber (Oxford: Pergamon Press) vol.31, pp 339–350

    Google Scholar 

  • Torok I, Hartenstein K, Kalmes A, Schmitt R, Strand D and Mechier B M 1993 a The l(2)gl homologue ofDrosophila pseudoobscura suppresses tumorigenicity in transgenicDrosophila melanogaster;Oncogene 8 1537–1549

    PubMed  CAS  Google Scholar 

  • Torok T, Tick G, Alvarado M and Kiss I 1993bP-lacW insertional mutagenesis on the second chromosome ofDrosophila melanogaster: Isolation of lethal with different overgrowth phenotypes;Genetics 135 71–80

    PubMed  CAS  Google Scholar 

  • Szabad J, Jursnich V and Bryant P J 1991 Requirement for cell-proliferation control genes inDrosophila oogenesis;Genetics 127 525–533

    PubMed  CAS  Google Scholar 

  • Tomotsune D, Shoji H, Wakamatsu Y, Kondoh H and Takahashi N 1993 A mouse homologue of theDrosophila tumour-suppressor gene l(2)gl controlled by Hox-C8in vivo;Nature (London) 365 69–72

    Article  CAS  Google Scholar 

  • vander Bliek A M and Meyerowitz E M 1991 Dynamin-like protein encoded by theDrosophila shibire gene associated with vesicular traffic;Nature (London) 411–414

  • Wallace M R, Marchuk D A, Andersen L B, Letcher R, Odeh H M, Saulino A M, Fountain J W, Brereton A, Nicholson J, Mitchell A L, Brownstein B H and Collins F S 1990 Type 1 neurofibromatosis gene: Identification of a large transcript disrupted in three NF1 patients;Science 249 181–186

    Article  PubMed  CAS  Google Scholar 

  • Watson K L, Johnson, T K and Denell R B 199ILethal(1)abberrant immune response mutations leading to inelanotic tumor formation inDrosophila melanogaster;Dev. Genet. 12 173–187

    Article  Google Scholar 

  • Watson K L, Konrad D K, Woods D F and Bryant P J 1992 TheDrosophila homolog of the human S6 ribosomal protein is required for tumor suppression in the haemalopoietic system;Proc. Natl. Acad. Sci. USA (in press)

  • Woods D F and Bryant P J 1989 Molecular cloning of the lethal(2)discslarge-I oncogene ofDrosophila;Bev. Biol. 134 222–235

    CAS  Google Scholar 

  • Woods D F and Bryant P J 1991 Thediscs-large tumor suppressor gene ofDrosophila encodes a guanylate kinase homolog localized at septate junctions;Cell 66 451–464

    Article  PubMed  CAS  Google Scholar 

  • Xu G, Lin B, Tanaka K, Dunn D, Wood D, Gesteland R, White R, Weiss R and Tamanoi F 1990 The catalytic domain of the neurofibroniatosis type 1 gene product stimulatesras GTPase and complementsira mutants ofS. cerevisiae;Cell 63 835–841

    Article  PubMed  CAS  Google Scholar 

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Mechler, B.M. When the control is lacking—the role of tumour suppressor genes in cancer development. J Biosci 19, 537–556 (1994). https://doi.org/10.1007/BF02703201

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