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Drosophila awdK–pn, a homologue of the metastasis suppressor gene nm23, suppresses the Tum–I haematopoietic oncogene

Abstract

The human nm23–H1 gene is a suppressor of solid tumour metastasis in some types of cancer. It is known that nm23 genes encode nucleoside diphosphate kinase polypeptides, but the regulatory pathways involving Nm23 are unclear. One approach to understanding nm23 function is to identify loci which interact with nm23. The Drosophila awd gene, a homologue of nm23, provides a model system for this genetic analysis. We report that the dominant awdK–pn allele suppresses haematopoietic defects associated with the Tum–I oncogene. Premature differentiation and aggregation of Tum–I blood cells is reduced by awdK–pn, resulting in an increased survival of Tum–I hemizygotes. Tum–I lethality is also suppressed by pn mutations, indicating the existence of a haematopoietic regulatory pathway involving the Tum–I, AwdK–pn and Pn proteins.

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References

  1. Liotta, L.A., Steeg, P.S. & Stetler-Stevenson, W.G. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64, 327–336 (1991).

    Article  CAS  Google Scholar 

  2. Evans, C.W. A genetic basis for metastasis. Cell Biol. int. Rep. 15, 1175–1179 (1991).

    Article  CAS  Google Scholar 

  3. Bevilaqua, G., Sobel, M.E., Liotta, L.A. & Steeg, P.A. Association of low nm23 RNA levels in human primary infiltrating ductal breast carcinomas with lymph node involvement and other histopathological indicators of high metastatic potential. Cancer Res. 49, 5185–5190 (1989).

    Google Scholar 

  4. Hennessy, C. et al. Expression of the anti-metastatic gene nm23 in human breast cancer; association with good prognosis. J. natn. Cancer Inst. 83, 281–285 (1991).

    Article  CAS  Google Scholar 

  5. Steeg, P.S. et al. Evidence for a novel gene associated with low tumour metastatic potential. J. natn. Cancer Inst. 80, 200–204 (1988).

    Article  CAS  Google Scholar 

  6. Steeg, P.S. et al. Altered gene expression in tumour metastasis: the nm23 gene. In Cancer Metastasis (eds Schirrmacher, V. & Schwartz-Albiez, R.) 48–52 (Springer, Heidelberg, 1989).

    Chapter  Google Scholar 

  7. Steeg, P.S., Bevilacqua, G., Pozzatti, R., Liotta, L.A. & Sobel, M.E. Altered expression of nm23, a gene associated with low tumour metastatic potential, during adenovirus2 E1a inhibition of experimental metastasis. Cancer Res. 48, 6550–6554 (1988).

    CAS  PubMed  Google Scholar 

  8. Okabe-Kado, J. et al. Identity of a differentiation inhibiting factor for mouse myeloid leukaemia cells with nm23/nucleoside diphosphate kinase. Biochem. Biophys. Res. Commun. 182, 987–994 (1992).

    Article  CAS  Google Scholar 

  9. Keim, D. et al. Proliferation-related expression of p19/nm23 nucleoside diphosphate kinase. J. clin. Invest. 89, 919–924 (1992).

    Article  CAS  Google Scholar 

  10. Stahl, J.A. et al. Identification of a second human nm23 gene, nm23-H2. Cancer Res. 51, 445–449 (1991).

    CAS  PubMed  Google Scholar 

  11. Gilles, A.-M., Presecan, E., Vonica, A. & Lascu, I. Nucleoside diphosphate kinase from human erythrocytes. J. biol. Chem. 266, 8784–8789 (1991).

    CAS  Google Scholar 

  12. Parks, S., & Agarwal, R. Nucleoside diphosphokinase. In The Enzymes (ed. Boyer, P.D.) 307–344 (Academic, New York, 1973).

    Google Scholar 

  13. Dearolf, C.R., Tripoulas, N., Biggs, J. & Shearn, A. Molecular consequences of awdb3, a cell-autonomous lethal mutation of Drosophila induced by hybrid dysgenesis. Dev. Biol. 129, 169–178 (1988).

    Article  CAS  Google Scholar 

  14. Wallet, V. et al. Dictyostelium nucleoside diphosphate kinase highly homologous to nm23 and awd proteins involved in mammalian tumour metastasis and development. J. natn. Cancer Inst. 18, 1199–1202 (1990).

    Article  Google Scholar 

  15. Munoz-Dorada, J., Inouye, M. & Inouye, S. Nucleoside diphosphate kinase from Myxococcus xanthus. I. Cloning and sequencing of the gene. J. Biol. Chem. 265, 2702–2706 (1990).

    Google Scholar 

  16. Kimura, N., Shimada, N., Nomura, K. & Watanabe, K. Isolation and characterization of a cDNA clone encoding rat nucleoside diphosphate kinase. J. biol. Chem. 265, 15744–15749 (1990).

    CAS  PubMed  Google Scholar 

  17. Nomura, T. et al. The amino acid sequence of nucleoside diphosphate kinase I from spinach leaves, as deduced from the cDNA sequence. Arch. Biochem. Biophys. 297, 42–45 (1992).

    Article  CAS  Google Scholar 

  18. Dearolf, C.R., Hersperger, E. & Shearn, A. Developmental consequences of awdb3, a cell-autonomous lethal mutation of Drosophila induced by hybrid dysgenesis. Dev. Biol. 129, 159–168 (1988).

    Article  CAS  Google Scholar 

  19. Rosengard, A.R. et al. Reduced nm23/awd protein in tumour metastasis and aberrant Drosophila development. Nature 342, 177–180 (1988).

    Article  Google Scholar 

  20. Biggs, J., Tripoulas, N., Hersperger, E., Dearolf, C. & Shearn, A. Analysis of the lethal interaction between the prune and Killer of prune mutations of Drosophila. Genes Dev. 2, 1333–1343 (1988).

    Article  CAS  Google Scholar 

  21. Sturtevant, A.H. A highly specific complementary lethal system in Drosophila melanogaster. Genetics 41, 118–123 (1956).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Corwin, H.O. & Hanratty, W.P. Characterization of a unique lethal tumourous mutation in Drosophila. Molec. gen. Genet. 14, 345–347 (1976).

    Article  Google Scholar 

  23. Silvers, M. & Hanratty, W.P. Alterations in the production of haemocytes due to a neoplastic mutation of Drosophila melanogaster. J. Invert. Path. 44, 324–328 (1984).

    Article  CAS  Google Scholar 

  24. Hanratty, W.P. & Ryerse, J.S. A genetic melanotic neoplasm of Drosophila melanogaster. Devl. Biol. 83, 238–249 (1981).

    Article  CAS  Google Scholar 

  25. Perrimon, N. & Mahowald, A.P. I(1) hopscotch, a larval-pupal zygotic lethal with a specific maternal effect on segmentation in Drosophila. Devl. Biol. 118: 28–41 (1986).

    Article  CAS  Google Scholar 

  26. Hanratty, W.P. & Dearolf, C.R., The Drosophila Tumourous-lethal haematopoietic oncogene is a dominant mutation in the hopscotch locus. Molec. gen. Genet. (in the press).

  27. Wilks, A.F. et al. Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Molec. cell. Biol. 11, 2057–2065 (1991).

    Article  CAS  Google Scholar 

  28. Rizki, T.M. Alterations in the haemocyte population of Drosophila melanogaster. J. Morph. 100, 437–458 (1957).

    Article  Google Scholar 

  29. Rizki, T.M. Experimental analysis of haemocyte morphology in insects. Am. Zool. 2, 247–256 (1962).

    Article  Google Scholar 

  30. Sparrow, J.C. Melanotic tumours. In The Genetics and Biology of Drosophila, Vol 2B (eds Ashburner, M. & Wright, T.R.F.) 277–313 (Academic, New York, 1978).

    Google Scholar 

  31. Watson, K.L., Johnson, T.K. & Dennell, R.E. Lethal(1)aberrant immune response mutations leading to melanotic tumour formation in Drosophila melanogaster. Dev. Genet. 12, 173–187 (1991).

    Article  CAS  Google Scholar 

  32. Hackstein, J.H.P. The lethal prune/Killer of prune interaction of Drosophila causes a syndrome resembling human neurofibromatosis (NF1). Eur. J. cell Biol. 58, 429–444 (1992).

    CAS  PubMed  Google Scholar 

  33. Salt, G. The cellular defence reaction of insects. Cambridge Monogr. exp. Biol. Vol 16 (Cambridge University Press, Cambridge, 1970).

    Google Scholar 

  34. Bryant, P.J. & Sang, J.H. Physiological genetics of melanotic tumours in Drosophila melanogaster. VI. The tumourigenic effects of juvenile hormone-like substances. Genetics 62, 321–336 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Rizki, T.M. Tumour formation in relation to metamorphosis in Drosophila melanogaster. J. Morph. 100, 459–472 (1957).

    Article  Google Scholar 

  36. Lascu, I., Chaffotte, A., Limbourg-Bouchon, B. & Veron, M. A pro/ser substitution in nucleoside diphosphate kinase of Drosophila melanogaster (mutation Killer of prune) affects stability but not catalytic efficiency of the enzyme. J. biol. Chem. 267, 12775–12781 (1992).

    CAS  Google Scholar 

  37. Teng, D.H.F., Engele, C.M. & Venkatesh, T.R. A product of the prune locus of Drosophila is similar to mammalian GTPase-activating protein. Nature 353, 437–440 (1991).

    Article  CAS  Google Scholar 

  38. Evans, B.A. & Howells, A.J. Control of drosopterin synthesis in Drosophila melanogaster mutants showing an altered pattern of GTP cyclohydrolase activity during development. Biochem. Genet. 16, 13–26 (1978).

    Article  CAS  Google Scholar 

  39. Mackey, W. & O'Donnell, J.M. A genetic analysis of the pteridine biosynthetic enzyme, guanosine triphosphate cyclohydrolase, in Drosophila melanogaster. Genetics 105, 35–53 (1983).

    Google Scholar 

  40. Barnes, T.M. & Burglin, T.R. Prune function? Nature 355, 504–505 (1992).

    Article  CAS  Google Scholar 

  41. Lindsley, D.L. & Zimm, G.G. The Genome of Drosophila melanogaster. (Academic, San Diego, 1992).

    Chapter  Google Scholar 

  42. Bodenstein, D. The postembryonic development of Drosophila. In Biology of Drosophila, (ed. Demerec, M.) 274–367 (Wiley, New York 1950).

    Google Scholar 

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Zinyk, D., McGonnigal, B. & Dearolf, C. Drosophila awdK–pn, a homologue of the metastasis suppressor gene nm23, suppresses the Tum–I haematopoietic oncogene. Nat Genet 4, 195–201 (1993). https://doi.org/10.1038/ng0693-195

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