Skip to main content

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.

  • Original Paper
  • Published:

Lats2, a putative tumor suppressor, inhibits G1/S transition

Abstract

Lats2 is a new member of the Lats tumor suppressor family. The human LATS2 gene is located at chromosome 13q11–12, which has been shown to be a hot spot (67%) for LOH in nonsmall cell lung cancer. In order to understand the function of LATS2 in the control of tumor development, we ectopically expressed mouse Lats2 via retroviral infection in NIH3T3/v-ras cells to examine whether Lats2 plays a role in suppressing tumor development and regulating cell proliferation. We have found that ectopic expression of Lats2 in NIH3T3/v-ras cells suppresses development of tumors in athymic nude mice and inhibits proliferation of NIH3T3/v-ras cells in an in vitro assay. Cell cycle profile analysis demonstrated that ectopic expression of Lats2 inhibited the G1/S transition. Further mechanistic studies revealed that cyclin E/CDK2 kinase activity was downregulated in Lats2-transduced NIH3T3/v-ras cells, while other cell cycle regulators controlling the G1/S transition were not affected. We have also shown that LATS2 kinase activity and two LATS conserved domains (LCDs) are required for Lats2 to suppress tumorigenicity and to inhibit cell growth. In addition, the LATS2 protein is cytoplasmic during interphase in NIH3T3 cells, while it becomes localized to the mitotic apparatus during mitosis. Finally, we propose a model in which a combination of mammalian Lats2 and Lats1 control cell proliferation by negatively regulating different cell cycle check points.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 4
Figure 1
Figure 2
Figure 3
Figure 5
Figure 6

Similar content being viewed by others

References

  • Aftab DT, Kwan J and Martin GS . (1997). Proc. Natl. Acad. Sci. USA, 94, 3028–3033.

  • Bartek J and Lukas J . (2001). FEBS Lett., 490, 117–122.

  • Blomberg I and Hoffmann I . (1999). Mol. Cell. Biol., 19, 6183–6194.

  • Blow JJ . (2001). EMBO J., 20, 3293–3297.

  • Ekholm SV and Reed SI . (2000). Curr. Opin. Cell. Biol., 12, 676–684.

  • Falck J, Mailand N, Syljuasen RG, Bartek J and Lukas J . (2001). Nature, 410, 842–847.

  • Falck J, Petrini JH, Williams BR, Lukas J and Bartek J . (2002). Nat. Genet., 30, 290–294.

  • Girard L, Zochbauer-Muller S, Virmani AK, Gazdar AF and Minna JD . (2000). Cancer Res., 60, 4894–4906.

  • Gu Y, Turck CW and Morgan DO . (1993). Nature, 366, 707–710.

  • Hanks SK, Quinn AM and Hunter T . (1988). Science, 241, 42–52.

  • Hirota T, Morisaki T, Nishiyama Y, Marumoto T, Tada K, Hara T, Masuko N, Inagaki M, Hatakeyama K and Saya H . (2000). J. Cell. Biol., 149, 1073–1086.

  • Hori T, Takaori-Kondo A, Kamikubo Y and Uchiyama T . (2000). Oncogene, 19, 3101–3109.

  • Justice RW, Zilian O, Woods DF, Noll M and Bryant PJ . (1995). Genes Dev., 9, 534–546.

  • McGowan CH and Russell P . (1993). EMBO J., 12, 75–85.

  • Molinari M, Mercurio C, Dominguez J, Goubin F and Draetta GF . (2000). EMBO Rep., 1, 71–79.

  • Morgan DO . (1995). Nature, 374, 131–134.

  • Morinaga N, Shitara Y, Yanagita Y, Koida T, Kimura M, Asao T, Kimijima I, Takenoshita S, Hirota T, Saya H and Kuwano H . (2000). Int. J. Oncol., 17, 1125–1129.

  • Nishiyama Y, Hirota T, Morisaki T, Hara T, Marumoto T, Iida S, Makino K, Yamamoto H, Hiraoka T, Kitamura N and Saya H . (1999). FEBS Lett., 459, 159–165.

  • Pear WS, Miller JP, Xu L, Pui JC, Soffer B, Quackenbush RC, Pendergast AM, Bronson R, Aster JC, Scott ML and Baltimore D . (1998). Blood, 92, 3780–3792.

  • Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H and Elledge SJ . (1997). Science, 277, 1497–1501.

  • Sherr CJ . (1996). Science, 274, 1672–1677.

  • Sherr CJ and Roberts JM . (1999). Genes Dev., 13, 1501–1512.

  • St John MA, Tao W, Fei X, Fukumoto R, Carcangiu ML, Brownstein DG, Parlow AF, McGrath J and Xu T . (1999). Nat. Genet., 21, 182–186.

  • Tao W, Zhang S, Turenchalk GS, Stewart RA, St John MA, Chen W and Xu T . (1999). Nat. Genet., 21, 177–181.

  • Wright JH, Munar E, Jameson DR, Andreassen PR, Margolis RL, Seger R and Krebs EG . (1999). Proc. Natl. Acad. Sci. USA, 96, 11335–11340.

  • Xia H, Qi H, Li Y, Pei J, Barton J, Blackstad M, Xu T and Tao W . (2002). Oncogene, 21, 1233–1241.

  • Xu T, Wang W, Zhang S, Stewart RA and Yu W . (1995). Development, 121, 1053–1063.

  • Yabuta N, Fujii T, Copeland NG, Gilbert DJ, Jenkins NA, Nishiguchi H, Endo Y, Toji S, Tanaka H, Nishimune Y and Nojima H . (2000). Genomics, 63, 263–270.

  • Yang X, Li DM, Chen W and Xu T . (2001). Oncogene, 20, 6516–6523.

Download references

Acknowledgements

We are grateful to Dr Catherine Verfaillie for her support and helpful advice for this research. We thank Dr Tian Xu at Yale University for Lats2 cDNA clone and anti-LATS2 antibody. We thank Dr Robert Sheaff for critical manuscript readings and antibodies, Dr Richard Jove for the NIH3T/v-ras cell line and Dr Robert Kratzke for the human lung cancer cell lines, H661 and H460. We also thank Huilin Qi for a lot of valuable discussion and technical help and Tishonna Woods for editing of the manuscript, and Julie Prebyl and Janet Peller for their assistance with FACS and data analyses. This work is supported by the startup fund for W Tao from the Department of Medicine and Stem Cell Institute, a Medical School Faculty Grant from Minnesota Medical Foundation, an American Cancer Society Institutional Research Grant (IRG-58-001-40-IRG40) and Research Scholar Grant from the American Cancer Society (RSG-02-065-01-MGO).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wufan Tao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, Y., Pei, J., Xia, H. et al. Lats2, a putative tumor suppressor, inhibits G1/S transition. Oncogene 22, 4398–4405 (2003). https://doi.org/10.1038/sj.onc.1206603

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206603

Keywords

This article is cited by

Search

Quick links