Largen: a molecular regulator of mammalian cell size control

Mol Cell. 2014 Mar 20;53(6):904-15. doi: 10.1016/j.molcel.2014.02.028.

Kazuo Yamamoto ¹, Valentina Gandin ², Masato Sasaki ¹, Susan McCracken ¹, Wanda Li ¹, Jennifer Liepa Silvester ¹, Andrew J Elia ¹, Feng Wang ³, Yosuke Wakutani ⁴, Roumiana Alexandrova ⁵, Yathor D Oo ⁶, Peter J Mullen ⁷, Satoshi Inoue ¹, Momoe Itsumi ¹, Valentina Lapin ¹, Jillian Haight ¹, Andrew Wakeham ¹, Arda Shahinian ¹, Mitsuhiko Ikura ³, Ivan Topisirovic ², Nahum Sonenberg ⁸, Tak W Mak ⁹

Affiliations

1 The Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada; Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
2 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, and Department of Oncology, McGill University, Montreal, QC H3T 1E2, Canada.
3 Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Signaling Biology, Ontario Cancer Institute, Toronto, ON M5G 1L7, Canada.
4 Department of Neurology, Kurashiki Heisei Hospital, Kurashiki, Okayama 710-0826, Japan.
5 The Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada.
6 Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
7 Division of Cancer Genomics and Proteomics, Ontario Cancer Institute, Toronto, ON M5G 2M9, Canada.
8 Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
9 The Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2C1, Canada; Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: tmak@uhnresearch.ca.

PMID: 24656129 DOI: 10.1016/j.molcel.2014.02.028

Abstract

Little is known about how mammalian cells maintain cell size homeostasis. We conducted a novel genetic screen to identify cell-size-controlling genes and isolated Largen, the product of a gene (PRR16) that increased cell size upon overexpression in human cells. In vitro evidence indicated that Largen preferentially stimulates the translation of specific subsets of mRNAs, including those encoding proteins affecting mitochondrial functions. The involvement of Largen in mitochondrial respiration was consistent with the increased mitochondrial mass and greater ATP production in Largen-overexpressing cells. Furthermore, Largen overexpression led to increased cell size in vivo, as revealed by analyses of conditional Largen transgenic mice. Our results establish Largen as an important link between mRNA translation, mitochondrial functions, and the control of mammalian cell size.

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