title: N-terminal truncation of Lats1 causes abnormal cell growth control and chromosomal instability.
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 (Lats1(ΔN/ΔN)). Some Lats1(ΔN/ΔN) mice were born safely and grew normally. However, mouse embryonic fibroblasts (MEFs) from Lats1(ΔN/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. Lats1(ΔN/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 Lats1(ΔN/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.
authors.affiliation: Department of Molecular Genetics, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Yabuta
authors.forename: Satomi
authors.initials: S
authors.lastname: Mukai
authors.forename: Ayumi
authors.initials: A
authors.lastname: Okamoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Okuzaki
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Kosuke
authors.initials: K
authors.lastname: Torigata
authors.forename: Kaori
authors.initials: K
authors.lastname: Yoshida
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Okada
authors.forename: Daisaku
authors.initials: D
authors.lastname: Miura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
authors.forename: Masahito
authors.initials: M
authors.lastname: Ikawa
authors.forename: Masaru
authors.initials: M
authors.lastname: Okabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nojima
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases