N-terminal truncation of Lats1 causes abnormal cell growth control and chromosomal instability

Norikazu Yabuta, Satomi Mukai, Ayumi Okamoto, Daisuke Okuzaki, Hirokazu Suzuki, Kosuke Torigata, Kaori Yoshida, Nobuhiro Okada, Daisaku Miura, Akihiko Ito, Masahito Ikawa, Masaru Okabe, Hiroshi Nojima

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21 Citations (Scopus)

Abstract

The tumor suppressors Lats1 and Lats2 are mediators of the Hippo pathway that regulates tissue growth and proliferation. Their N-terminal non-kinase regions are distinct except for Lats conserved domains 1 and 2 (LCD1 and LCD2), which may be important for Lats1/2-specific functions. Lats1 knockout mice were generated by disrupting the N-terminal region containing LCD1 (Lats1δN/δN). Some Lats1δN/δN mice were born safely and grew normally. However, mouse embryonic fibroblasts (MEFs) from Lats1δN/δN mice displayed mitotic defects, centrosomal overduplication, chromosomal misalignment, multipolar spindle formation, chromosomal bridging and cytokinesis failure. They also showed anchorage-independent growth and continued cell cycles and cell growth, bypassing cell-cell contact inhibition similar to tumor cells. Lats1δN/δN MEFs produced tumors in nude mice after subcutaneous injection, although the tumor growth rate was much slower than that of ordinary cancer cells. Yap, a key transcriptional coactivator of the Hippo pathway, was overexpressed and stably retained in Lats1δN/δN MEFs in a cell density independent manner, and Lats2 mRNA expression was downregulated. In conclusion, N-terminally truncated Lats1 induced Lats2 downregulation and Yap protein accumulation, leading to chromosomal instability and tumorigenesis.

Original languageEnglish
Pages (from-to)508-519
Number of pages12
JournalJournal of cell science
Volume126
Issue number2
DOIs
Publication statusPublished - Jan 2013

Keywords

  • Chromosome instability
  • Hippo
  • Lats1
  • Lats2
  • YAP

ASJC Scopus subject areas

  • Cell Biology

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    Yabuta, N., Mukai, S., Okamoto, A., Okuzaki, D., Suzuki, H., Torigata, K., Yoshida, K., Okada, N., Miura, D., Ito, A., Ikawa, M., Okabe, M., & Nojima, H. (2013). N-terminal truncation of Lats1 causes abnormal cell growth control and chromosomal instability. Journal of cell science, 126(2), 508-519. https://doi.org/10.1242/jcs.113431