Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction

Marcus, John; Tao, Wufan; Fei, Xiaolan; Fukumoto, Royd; Carcangiu, Maria Luisa; Brownstein, David G.; Parlow, Albert F.; McGrath, James; Xu, Tian

doi:10.1038/5965

Cited by 400 publications

(289 citation statements)

References 21 publications

Supporting

Mentioning

274

Contrasting

Order By: Relevance

“…Thus, although Lats2 is essential for embryonic development, 45,46 Lats1 knockout mice are viable. 47 Moreover, as shown here (Figure 6a), whereas Lats2 expression is strongly induced during differentiation, Lats1 expression is not. Lastly, we show that Lats1 expression in differentiating ESCs is affected neither by p53 levels nor p53 activity, both of which strongly affect ESC differentiation.…”

Section: Discussionmentioning

confidence: 51%

Lats2 is critical for the pluripotency and proper differentiation of stem cells

et al. 2014

View full text Add to dashboard Cite

Differentiation is a highly controlled process essential for embryonic and adult development. Moreover, disruption of proper differentiation is often associated with human diseases, including cancer. We analyzed the involvement of the tumor-suppressor Lats2 in mouse embryonic stem cell (mESC) pluripotency and differentiation, and report that mESCs lacking Lats2 are unable to sustain stemness and are not able to initiate and coordinate developmental transcriptional programs. Lats2 À / À mESCs retain bivalent 'poised' chromatin marks on developmental genes and exhibit germ layer ambiguity both in vitro and in vivo. Importantly, in coordinating proper germ layer specification, Lats2 engages in a feedback loop with another tumor suppressor, p53.

show abstract

Section: Discussionmentioning

confidence: 51%

Lats2 is critical for the pluripotency and proper differentiation of stem cells

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The Lats tumor suppressor family has been shown to play important roles in the control of tumor development and the cell cycles from flies (Justice et al, 1995;Xu et al, 1995) to human (Nishiyama et al, 1999;St John et al, 1999;Tao et al, 1999;Yang et al, 2001;Xia et al, 2002). Loss of function of Drosophila lats (or warts) results in tumor development in mosaic flies and causes embryonic or pupae lethality in lats homozygotes (Justice et al, 1995;Xu et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2003

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Two mammalian homologs, Lats1 and Lats2, have been identified. Lats1-deficient mice develop tumors (St John et al 1999). The gene encoding Lats2, also known as Kpm (Hori et al 2000;Yabuta et al 2000), resides in a chromosomal region that exhibits frequent loss of heterozygosity (LOH) in human cancers (Yabuta et al 2000), consistent with the idea that it, too, is a tumor suppressor.…”

mentioning

confidence: 99%

A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization

Aylon¹,

Michael²,

Shmueli³

et al. 2006

Genes Dev.

257

296

View full text Add to dashboard Cite

Damage to the mitotic spindle and centrosome dysfunction can lead to cancer. To prevent this, cells trigger a succession of checkpoint responses, where an initial mitotic delay is followed by slippage without cytokinesis, spawning tetraploid G1 cells that undergo a p53-dependent G1/S arrest. We describe the importance of Lats2 (Large Tumor Suppressor 2) in this checkpoint response. Lats2 binds Mdm2, inhibits its E3 ligase activity, and activates p53. Nocodazole, a microtubule poison that provokes centrosome/mitotic apparatus dysfunction, induces Lats2 translocation from centrosomes to the nucleus and p53 accumulation. In turn, p53 rapidly and selectively up-regulates Lats2 expression in G2/M cells, thereby defining a positive feedback loop. Abrogation of Lats2 promotes accumulation of polyploid cells upon exposure to nocodazole, which can be prevented by direct activation of p53. The Lats2-Mdm2-p53 axis thus constitutes a novel checkpoint pathway critical for the maintenance of proper chromosome number.[Keywords: Lats2; Mdm2; p53; tetraploidy checkpoint] Supplemental material is available at http://www.genesdev.org.

show abstract

Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction

Cited by 400 publications

References 21 publications

Lats2 is critical for the pluripotency and proper differentiation of stem cells

Lats2 is critical for the pluripotency and proper differentiation of stem cells

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

A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization

Contact Info

Product

Resources

About