LATS1 tumor suppressor regulates G2/M transition and apoptosis

Hong Xia, Huilin Qi, Yunfang Li, Jing Pei, James Barton, Mark Blackstad, Tian Xu, Wufan Tao

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

Abstract

The LATS1 gene is a mammalian member of the novel lats tumor suppressor family. Both lats mosaic flies and LATS1 deficient mice spontaneously develop tumors. Our previous studies have shown that inactivation of Drosophila lats leads to up-regulation of cyclin A in the fly, and the human LATS1 protein associates with CDC2 in early mitosis in HeLa cells, suggesting that the lats gene family may negatively regulate cell proliferation by modulating CDC2/Cyclin A activity. We demonstrate here that transduction of the human breast cancer cell MCF-7 with recombinant LATS1 adenovirus (Ad-LATS1), but not with EGFP adenovirus (AdEGFP), inhibits in vitro cell proliferation. Ectopic expression of LATS1 in MCF-7 cells specifically down-regulates Cyclin A and Cyclin B protein levels and dramatically reduces CDC2 kinase activity, leading to a G2/M blockade. Furthermore, Ad-LATS1 suppresses anchorage-independent growth of MCF-7 cells in soft agar and tumor formation in athymic nude mice. We also demonstrate that ectopic expression of LATS1 in MCF-7 cells and human lung cancer cell H460 upregulates the level of BAX proteins and induces apoptosis. Finally, we show that LATS1 kinase activity is required for its ability to inhibit cell growth and induce apoptosis. The results indicate that the LATS1 tumor suppressor may play an important role in the control of human tumor development and that LATS1 suppresses tumorigenesis by negatively regulating cell proliferation and modulating cell survival.

Original languageEnglish (US)
Pages (from-to)1233-1241
Number of pages9
JournalOncogene
Volume21
Issue number8
DOIs
StatePublished - 2002

Bibliographical note

Funding Information:
We are grateful to Dr Catherine Verfaillie for her support and helpful advice for this research. We thank Drs David Kiang, Douglas Yee and Robert Kratzke for critical manuscript readings, Drs Jeff Miller and Robert Kratzke for cell lines, Dr Robert Sheaff for antibodies, and Julie Prebyl and Janet Peller for their assistance for FACS and data analyses. This work is supported by the startup fund for W Tao from the Department of Medicine and Stem Cell Institute, Faculty Seed Grant from Academic Health Center, American Cancer Society Institutional Research Grant (IG-58-001-40-IRG40) to the University of Minnesota.

Keywords

  • Apoptosis
  • G2/M transition
  • LATS1
  • Tumor suppressor

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