Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity |
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Authors: | McPherson John Peter Tamblyn Laura Elia Andrew Migon Eva Shehabeldin Amro Matysiak-Zablocki Elzbieta Lemmers Bénédicte Salmena Leonardo Hakem Anne Fish Jason Kassam Farah Squire Jeremy Bruneau Benoit G Hande M Prakash Hakem Razqallah |
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Institution: | Division of Cellular & Molecular Biology, Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada. |
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Abstract: | The Drosophila melanogaster warts/lats tumour suppressor has two mammalian counterparts LATS1/Warts-1 and LATS2/Kpm. Here, we show that mammalian Lats orthologues exhibit distinct expression profiles according to germ cell layer origin. Lats2(-/-) embryos show overgrowth in restricted tissues of mesodermal lineage; however, lethality ultimately ensues on or before embryonic day 12.5 preceded by defective proliferation. Lats2(-/-) mouse embryonic fibroblasts (MEFs) acquire growth advantages and display a profound defect in contact inhibition of growth, yet exhibit defective cytokinesis. Lats2(-/-) embryos and MEFs display centrosome amplification and genomic instability. Lats2 localizes to centrosomes and overexpression of Lats2 suppresses centrosome overduplication induced in wild-type MEFs and reverses centrosome amplification inherent in Lats2(-/-) MEFs. These findings indicate an essential role of Lats2 in the integrity of processes that govern centrosome duplication, maintenance of mitotic fidelity and genomic stability. |
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Keywords: | centrosome embryonic lethality genomic instability Kpm Lats2 |
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