Skip to main content
See More

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity

Nature Genetics volume 21, pages 177–181 (1999)Cite this article

Abstract

We have previously used mosaic flies to screen for tumour suppressors or negative regulators of cell proliferation1. The cellular composition of these flies resembles that of cancer patients who are chimaeric individuals carrying a small number of mutated somatic cells. One of the genes we identified is the large tumour suppressor gene, lats (also known as wts), which encodes a putative serine/threonine kinase1,2. Somatic cells mutant for lats undergo extensive proliferation and form large tumours in many tissues in mosaic adults. Homozygous mutants for various lats alleles display a range of developmental defects including embryonic lethality1. Although many tumour suppressors have been identified in Drosophila melanogaster3,4,5,6,7, it is not clear whether these fly genes are directly relevant to tumorigenesis in mammals. Here, we have isolated mammalian homologues of Drosophila lats. Human LATS1 suppresses tumour growth and rescues all developmental defects, including embryonic lethality in flies. In mammalian cells, LATS1 is phosphorylated in a cell–cycle–dependent manner and complexes with CDC2 in early mitosis. LATS1–associated CDC2 has no mitotic cyclin partner and no kinase activity for histone H1. Furthermore, lats mutant cells in Drosophila abnormally accumulate cyclin A. These biochemical observations indicate that LATS is a novel negative regulator of CDC2/cyclin A, a finding supported by genetic data in Drosophila demonstrating that lats specifically interacts with cdc2 and cyclin A.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Human LATS1 and related proteins.
Figure 2: Human LATS1 can functionally replace Drosophila lats.
Figure 3: Phosphorylation of LATS1 and its association with CDC2 oscillate with the cell cycle.
Figure 4: Genetic interaction between lats and cdc2 in Drosophila .

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Xu, T. et al. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121, 1053–1063 (1995).

    CAS  PubMed  Google Scholar 

  2. Justice, R.W., Zilian, O., Woods, D.F., Noll, M. & Bryant, P.J. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev. 9, 534–546 (1995).

    Article  CAS  Google Scholar 

  3. Klämbt, C. et al. The Drosophila melanogaster l(2)gl gene encodes a protein homologous to the cadherin cell–adhesion molecule family. Dev. Biol. 133, 425–436 (1989).

    Article  Google Scholar 

  4. Mahoney, P.A. et al. The fat tumor suppressor gene in Drosophila encodes a novel member of the cadherin gene superfamily. Cell 67, 583–868 (1991).

    Article  Google Scholar 

  5. Woods, D. & Bryant, P.J. The Discs Large tumor suppressor gene of Drosophila encodes a guanylated kinase homolog localized at septate junction. Cell 66, 451– 464 (1991).

    Article  CAS  Google Scholar 

  6. Boedigheimer, M. & Laughon, A. expended: a gene involved in the control of cell proliferation in imaginal discs. Development 118, 1291–1301 (1993).

    CAS  PubMed  Google Scholar 

  7. Theodosiou, N.A., Zhang, S., Wang, W.Y. & Xu, T. shiva/slimb coordinates wg and dpp expression in the dorsal–ventral and anterior–posterior axes during limb development. Development 125, 3411–3416 ( 1998).

    CAS  PubMed  Google Scholar 

  8. Knehr, M. et al. A critical appraisal of synchronization methods applied to achieve maximal enrichment of HeLa cells in specific cell cycle phases. Exp. Cell Res. 217, 546–553 (1995).

    Article  CAS  Google Scholar 

  9. Draetta, G. & Beach, D. Activation of CDC2 protein kinase during mitosis in human cells: cell cycle–dependent phosphorylation and subunit rearrangement. Cell 54, 17– 26 (1988).

    Article  CAS  Google Scholar 

  10. Fields, S. & Song, O. A novel genetic system to detect protein–protein interactions. Nature 340, 245– 246 (1989).

    Article  CAS  Google Scholar 

  11. Finley, R.L. & Brent, R. in DNA Cloning: A Practical Approach: Expression Systems (eds Glover, D.M. & Hames, B.D.) 170– 203 (Oxford, New York, 1994).

    Google Scholar 

  12. Sun, Z. et al. Spk1/Rad53 is regulated by Mec1–dependent protein phosphorylation in DNA replication and damage checkpoint pathways. Genes Dev. 10, 395–406 (1996).

    Article  CAS  Google Scholar 

  13. Draetta, G. et al. Cdc2 protein kinase is complexed with both cyclin A and B: evidence for proteolytic inactivation of MPF. Cell 56, 829–838 (1989).

    Article  CAS  Google Scholar 

  14. Solomon, M.J., Glotzer, M., Lee, T.H., Philippe, M. & Kirschner, M.W. Cyclin activation of p34cdc2. Cell 63, 1013–1024 (1990).

    Article  CAS  Google Scholar 

  15. Sherr, C.J. Cancer cell cycles. Science 274, 1672– 1677 (1996).

    Article  CAS  Google Scholar 

  16. King, R.W., Jackson, P.K. & Kirschner, M.W. Mitosis in transition. Cell 79, 563–571 (1994).

    Article  CAS  Google Scholar 

  17. Clegg, N., Whitehead, I., Williams, J., Spiegelman, G. & Grigliatti, T. A developmental and molecular analysis of Cdc2 mutations in Drosophila melanogaster. Genome 36, 676–685 ( 1993).

    Article  CAS  Google Scholar 

  18. Toyn, J. & Johnston, L. The Dbf2 and Dbf20 protein kinases of budding yeast are activated after the metaphase to anaphase cell cycle transition. EMBO J. 13, 1103– 1113 (1994).

    Article  CAS  Google Scholar 

  19. Millward, T., Cron, P. & Hemmings, B. Molecular cloning and characterization of a conserved nuclear serine (threonine) protein kinase. Proc. Natl Acad. Sci. USA 92, 5022–5026 ( 1995).

    Article  CAS  Google Scholar 

  20. Hunter, T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell 80, 225– 236 (1995).

    Article  CAS  Google Scholar 

  21. Leitina, B., Svet–Moldavsky, G., Tumyan, B. & Zinzar, S. Enormous organ–like growth of transplants of fetal digestive tract. Transplantation 11, 499– 502 (1971).

    Article  CAS  Google Scholar 

  22. Bryant, P. in The Genetics and Biology of Drosophila (eds Ashburner, M. & Novitski, E.) PAGES? (Academic Press, New York, 1978).

    Google Scholar 

  23. Michalopoulos, G. & DeFrances, M. Liver regeneration. Science 276, 60–66 (1997).

    Article  CAS  Google Scholar 

  24. Wang, J., Chenivesse, X., Henglein, B. & Brechot, C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 343, 555–557 (1990).

    Article  CAS  Google Scholar 

  25. Keyomarsi, K. & Pardee, A. Redundant cyclin overexpression and gene amplification in breast cancer cell. Proc. Natl Acad. Sci. USA 90, 1112–1116 ( 1993).

    Article  CAS  Google Scholar 

  26. Arany, I., Rady, P., Evers, B.M., Tyring, S.K. & Townsend, C.M. Analysis of multiple molecular changes in human endocrine tumors. Surg. Oncol. 3, 153– 159(1994).

    Article  CAS  Google Scholar 

  27. St. John, M.A.R. et al. Mice deficient for Lats1 develop soft tissue sarcomas, ovarian tumours and pituitary dysfunction. Nature Genet. 21, 182–186 (1999).

    Article  CAS  Google Scholar 

  28. St. John, M.A.R. & Xu, T. Understanding human cancer in a fly? Am. J. Hum. Genet. 61, 1006–1010 (1997).

    Article  CAS  Google Scholar 

  29. Xu, T. & Rubin, G.M. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117 , 1223–1237 (1993).

    CAS  Google Scholar 

  30. Thomas, B.J., Gunning, D.A., Cho, J. & Zipursky, L. Cell cycle progression in the developing Drosophila eye: roughex encodes a novel protein required for the establishment of G1. Cell 77, 1003 –1014 (1994).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Zhang for advice; T. Grigliatti and C. Lehner for reagents; members of the Xu lab for comments; and W. Yu, T. Ding, X. Fei and K. Sepanek for assistance. W.T. was an Anna Fuller fellow. G.S.T. is an NSF graduate fellow. S.Z. and R.S. are YUF students. M.S.J. is a MSTP student. This work is supported in part by grants from NIH (R01CA69408) and the Patrick and Catherine Weldon Donaghue Medical Research Foundation.

Author information

Authors and Affiliations

  1. Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, 06536–0812, Connecticut, USA

    Wufan Tao, Sheng Zhang, Gregory S Turenchalk, Weili Chen & Tian Xu

  2. Department of Biology, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, 06536–0812, Connecticut, USA

    Rodney A Stewart

  3. Department of Cell Biology, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, 06536–0812, Connecticut , USA

    Maie A R St John

Authors
  1. Wufan Tao
    View author publications

    Search author on:PubMed Google Scholar

  2. Sheng Zhang
    View author publications

    Search author on:PubMed Google Scholar

  3. Gregory S Turenchalk
    View author publications

    Search author on:PubMed Google Scholar

  4. Rodney A Stewart
    View author publications

    Search author on:PubMed Google Scholar

  5. Maie A R St John
    View author publications

    Search author on:PubMed Google Scholar

  6. Weili Chen
    View author publications

    Search author on:PubMed Google Scholar

  7. Tian Xu
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Tian Xu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tao, W., Zhang, S., Turenchalk, G. et al. Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nat Genet 21, 177–181 (1999). https://doi.org/10.1038/5960

Download citation

  • Received:

  • Accepted:

  • Issue date:

  • DOI: https://doi.org/10.1038/5960

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing