251. N-terminal truncation of Lats1 causes abnormal cell growth control and chromosomal instability
- Author
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Ayumi Okamoto, Masahito Ikawa, Masaru Okabe, Nobuhiro Okada, Daisuke Okuzaki, Hiroshi Nojima, Satomi Mukai, Hirokazu Suzuki, Norikazu Yabuta, Kaori Yoshida, Akihiko Ito, Kosuke Torigata, and Daisaku Miura
- Subjects
Transcription, Genetic ,Carcinogenesis ,Down-Regulation ,Mice, Nude ,Cell Cycle Proteins ,Cell Growth Processes ,Protein Serine-Threonine Kinases ,Biology ,Mice ,Hippo ,Cell Line, Tumor ,Chromosomal Instability ,Chromosome instability ,Cell Adhesion ,Animals ,Humans ,Molecular Biology ,Mitosis ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,Genetics ,Mice, Inbred BALB C ,Hippo signaling pathway ,Cell growth ,Contact inhibition ,YAP-Signaling Proteins ,Cell Biology ,Cell cycle ,Phosphoproteins ,Molecular biology ,Cell biology ,Female ,YAP ,Multipolar spindles ,Lats1 ,Cytokinesis ,Signal Transduction ,Lats2 ,Developmental Biology - Abstract
Summary 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.
- Published
- 2013
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