Largen: A Molecular Regulator of Mammalian Cell Size Control

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.

Mitochondrial Function and Cell Size: An Allometric Relationship

“…Some of the metabolic pathways downstream of mitochondria can also decrease cellular catabolism more than 5 they reduce protein synthesis, causing an increase in cell size [12]. While mitochondria are clearly important for setting the overall metabolic activity of the cell, there is some controversy in which way mitochondrial perturbations affect animal cell size [13][14][15]. Inhibition of oxidative phosphorylation, induction of mitochondrial ROS and mild uncoupling of mitochondrial membrane potential increase cell size and reduce cell proliferation [13].…”

Mechanistic aspects of mammalian cell size control

“…The power of the PRR16 gene to increase cell size was also confirmed in HeLa and 293T cells transfected with a plasmid expressing a Myc‐tagged version of the PRR16 gene product (Yamamoto et al . ). Conversely, when expression of the PRR16 gene was knocked down by siRNA in Jurkat cells, as well as in other cell lines, cell size was decreased compared to control siRNA‐treated cells (Yamamoto et al .…”

“…To address this issue and to isolate genes controlling mammalian cell size, we designed a unique screen in which rapamycin treatment was combined with a novel genetic switch capable of randomly activating any gene in a mammalian cell genome (Yamamoto et al . ).…”

Cell mechanical microenvironment for cell volume regulation

“…Cells in vivo exist with a fixed range of volume, which is under strict regulation (Amodeo & Skotheim, ; Ginzberg et al, ; Hoffmann et al, ; Pan et al, ; K. Yamamoto et al, ). To investigate the mechanism for the cell to maintain its volume in a certain range, several growth factors and cytokines have been evaluated to elicit the variation in cell volume (Ginzberg et al, ; Hoffmann et al, ).…”

“…As one of the fundamental homeostasis in cell biology, the maintenance of cell volume in a certain range is associated with many important cell behaviors and functions (Amodeo & Skotheim, ; Ginzberg, Kafri, & Kirschner, ; Hoffmann, Lambert, & Pedersen, ; Lambert, Hoffmann, & Pedersen, ; Pan, Saunders, Flor‐Parra, Howard, & Chang, ; K. Yamamoto et al, ), for example, cell cycle regulation (Bates, ; Kiyomitsu, ; Tzur, Kafri, LeBleu, Lahav, & Kirschner, ), migration (Bates, ; Stroka et al, ), differentiation (Adapala et al, ; Li, Rycaj, Chen, & Tang, ; Pathak et al, ), and apoptosis (Lang & Hoffmann, ). For instance, suspension cells with larger cell volume exhibit a higher growth rate (Tzur et al, ).…”