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Lats2, a Putative Tumor Suppressor, Inhibits G1/S Transition

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Lats2, a Putative Tumor Suppressor, Inhibits G1/S Transition Oncogene (2003) 22, 4398–4405 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc Lats2, a putative tumor suppressor, inhibits G1/S transition Yunfang Li1,3, Jing Pei1,3, Hong Xia1, Hengning Ke1, Hongyan Wang1 and Wufan Tao*,1,2 1Stem Cell Institute, Division of Hematology, Oncology and Transplantation, 2Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA Lats2 is a new member of the Lats tumor suppressor (or warts) results in tumor development in mosaic flies family. The human LATS2 gene is located at chromosome and causes embryonic or pupae lethality in lats 13q11–12, which has been shown to be a hot spot (67%) homozygotes (Justice et al., 1995; Xu et al., 1995). for LOH in nonsmall cell lung cancer. In order to LATS1 (or WARTS1), a human homolog of Drosophila understand the function of LATS2 in the control of tumor lats, is able to rescue all developmental defects in lats development, we ectopically expressed mouse Lats2 via homozygous mutants and suppress tumor formation in retroviral infection in NIH3T3/v-ras cells to examine lats mosaic flies (Tao et al., 1999). Lats1-deficient female whether Lats2 plays a role in suppressing tumor develop- mice spontaneously develop soft tissue sarcomas and ment and regulating cell proliferation. We have found that ovarian stromal cell tumors, demonstrating that the ectopic expression of Lats2 in NIH3T3/v-ras cells Lats1 gene functions as a tumor suppressor in mice (St suppresses development of tumors in athymic nude mice John et al., 1999). No somatic mutations in the LATS1 and inhibits proliferation of NIH3T3/v-ras cells in an in coding region have been identified by RT–PCR SSCP vitro assay. Cell cycle profile analysis demonstrated that analysis of 25breast cancer samples, although this also ectopic expression of Lats2 inhibited the G1/S transition. does not rule out the possibility that LATS1 may be Further mechanistic studies revealed that cyclin E/CDK2 inactivated in human breast tumors by other epigenetic kinase activity was downregulated in Lats2-transduced mechanisms such as methylation (Morinaga et al., NIH3T3/v-ras cells, while other cell cycle regulators 2000). controlling the G1/S transition were not affected. We Mechanistic studies on LATS1 revealed that it might have also shown that LATS2kinase activity and two control tumorigenesis by negatively regulating the cell LATS conserved domains (LCDs) are required for Lats2 cycle. The LATS1 protein associates with a major to suppress tumorigenicity and to inhibit cell growth. In mitotic kinase, CDC2, at G2/M transition or in early addition, the LATS2protein is cytoplasmic during mitosis in HeLa cells. CDC2, when associated with interphase in NIH3T3 cells, while it becomes localized LATS1, was found to be inactive for its kinase activity to the mitotic apparatus during mitosis. Finally, we (Tao et al., 1999). Loss of function of lats in Drosophila propose a model in which a combination of mammalian resulted in the upregulation of Cyclin A (Tao et al., Lats2 and Lats1 control cell proliferation by negatively 1999). Ectopic expression of Lats1 in human cancer cell regulating different cell cycle check points. lines leads to the downregulation of Cyclin A and Cyclin Oncogene (2003) 22, 4398–4405. doi:10.1038/sj.onc.1206603 B at the protein level (Xia et al., 2002) and/or inactivation of CDC2 kinase, thereby blocking cells at Keywords: Lats2; tumor suppressor; G1/S transition; G2/M and preventing tumor development in nude mice cell cycle (Yang et al., 2001; Xia et al., 2002). Microinjection of a truncated human LATS1 protein (a.a 136–700) inter- fered with the localization of zyxin to the mitotic apparatus and lengthened mitosis (Hirota et al., 2000). Introduction Ectopic expression of LATS1 in human tumor cell lines has also been shown to induce apoptosis by upregulat- The Lats tumor suppressor family has been shown to ing the level of BAX protein (Xia et al., 2002) or play important roles in the control of tumor develop- upregulating Caspase-3 activity (Yang et al., 2001), ment and the cell cycles from flies (Justice et al., 1995; indicating that LATS1 may also control tumorigenesis Xu et al., 1995) to human (Nishiyama et al., 1999; by inducing apoptosis. St John et al., 1999; Tao et al., 1999; Yang et al., 2001; Lats2 (Yabuta et al., 2000), also known as KPM Xia et al., 2002). Loss of function of Drosophila lats (Hori et al., 2000), is the second mammalian member of the Lats tumor suppressor gene family. Human LATS2 *Correspondence: W Tao, MMC716, 420 Delaware Street SE, has been mapped onto human chromosome 13q11–12 University of Minnesota, Minneapolis, MN 55455, USA; (Yabuta et al., 2000), a hot spot (67%) for LOH in E-mail: [email protected] nonsmall cell lung cancer (Girard et al., 2000). Lats2 3These two authors contribute equally Received 11 October 2002; revised 5March 2003; accepted 21 March encodes a putative Ser/Thr protein kinase. The LATS2 2003 protein shares 85% and 75% sequence identity to Lats 2, a putative tumor suppressor YLiet al 4399 human LATS1 and Drosophila lats proteins in the kinase domain (Hori et al., 2000; Yabuta et al., 2000). Although the overall sequence similarity in the amino terminus between mammalian LATS1 and LATS2 proteins is low, two stretches of highly conserved sequence (B50% identical amino acids) are identifiable (Hori et al., 2000 and Figure 4d). The function of these two conserved domains remains to be unveiled. Although the human LATS2 protein is claimed to be phosphorylated in mitosis, transient transfection of wild-type Lats2 and mutant Lats2K697A (kinase-inactive) Figure 1 Lats2 suppresses v-ras-mediated tumorigenicity of into 293 and HeLa cells revealed no information about NIH3T3 cells and inhibits cell proliferation. (a) Expression of the role of Lats2 in the control of cell proliferation and/ exogenous LATS2 protein in NIH3T3/v-ras cells. Exogenous or the cell cycle (Hori et al., 2000). Therefore, it is LATS2 proteins detected by Western blot in NIH3T3/v-ras cells unknown if the LATS2 gene functions as a tumor with anti-MYC antibodies: (1) in NIH3T3/v-ras cells without virus infection, (2) in MIGR1-Lats2-transduced NIH3T3/v-ras cells suppressor. It is also unclear if LATS1 and LATS2 play without enrichment and (3) in MIGR1-Lats2-transduced different roles in the control of tumor development and NIH3T3/v-ras cells enriched by FACS. Equal amounts of proteins the cell cycle. Here, we present evidence that Lats2 has a were loaded. (b) Exogenous Lats2 suppresses anchorage-indepen- tumor suppressor function by showing that ectopic dent growth of NIH3T3/v-ras cells in soft agar. Colonies derived expression of Lats2 suppresses tumorigenicity of from 500 cells that were infected by MIGR1 (left) or MIGR1-Lats2 (right) were grown for 3 weeks in the soft agar. (c) Growth NIH3T3/v-ras cells and inhibits cell growth. Interest- inhibition assay. In total, 7000 of the Lats2-transduced NIH3T3/v- ingly, we found that Lats2 controls cell proliferation by ras cells or control cells were plated in a 6 cm dish. Total cell negatively regulating the G1/S transition, which is numbers were counted daily for 7 days. Experiments were repeated different from the G2/M blockage imposed by LATS1. more than three times Our studies reveal that ectopic expression of Lats2 results in a downregulation of Cyclin E/CDK2 kinase activity. We also demonstrate that LATS2 kinase Lats2 was measured in soft agar, and tumor develop- activity and two LATS conserved domains (LCDs) are ment in athymic nude mice was examined. We found required for its ability to inhibit cell proliferation and that expression of Lats2 in NIH3T3/v-ras cells drama- tumorigenicity. Finally, we show that the LATS2 tically suppressed colony growth of NIH3T3/v-ras cells protein is cytoplasmic during interphase, while it also in soft agar as compared to the control (Figure 1b). locates to the mitotic apparatus during mitosis. Ectopic expression of LATS2 in NIH3T3/v-ras cells also suppressed v-ras-mediated tumorigenesis in athymic nude mice. Our results showed that Lats2-transduced NIH3T3/v-ras cells failed to develop tumors in nude Results mice (six out of six) 2 weeks after inoculation, while control virus-transduced cells developed large tumors in Expression of exogenous Lats2 gene in NIH3T3 cells mice (six out of six). These studies demonstrate that In order to study the role of Lats2 in the control of ectopic expression of Lats2 suppressed the anchorage- tumorigenesis and cell proliferation, a replication- independent growth of NIH3T3/v-ras cells in soft agar defective retrovirus, MIGR1-Lats2, was generated (see and the tumorigenicity of NIH3T3/v-ras cells in vivo, Materials and methods), in which the LATS2 protein indicating that Lats2 may play a role in preventing and EGFP are coexpressed as a bicistron. The expres- tumor development. sion of endogenous LATS2 protein cannot be detected by Western blot in either NIH3T3/v-ras cells (data not Lats2 inhibits cell proliferation by blocking G1/S shown) or its parental cell, NIH3T3 (Yabuta et al., transition 2000). The expression of exogenous Lats2 was con- firmed by Western blot in Lats2-transduced NIH3T3/ To understand the mechanism(s) by which the expres- v-ras cells (Figure 1a, lanes 2 and 3). Using EGFP as a sion of Lats2 suppresses the tumorigenicity of NIH3T3/ marker, retrovirus-transduced cells can be enriched by v-ras cells, we examined the effects of ectopic expression FACS for further analysis (Figure 1a). All retrovirus- of Lats2 on cell proliferation. As shown in Figure 1c, infected cells used in the following experiments were growth of Lats2-transduced NIH3T3/v-ras cells was enriched by FACS.
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