ReviewWhy size matters: altering cell size
Section snippets
Introduction: processes affecting cell size
The maintenance of cell size requires homeostasis between macromolecule synthesis and degradation and, in multicellular systems, is intimately linked to nutrient and growth factor availability. As environmental conditions change, cells can reduce and restore their size. When nutrients and growth factors are saturating, however, there appears to be a limit to the maximum size a given cell type can reach. The metabolic potential of a cell likely parallels its DNA content and indeed there is a
Growth factor signaling through InR/PI3K
In the past few years, an exhaustive genetic dissection in Drosophila has validated the role of the insulin/PI3-kinase (PI3K) pathway in growth control (Fig. 2). PI3K is recruited to an activated insulin receptor (InR) through an insulin receptor substrate and an adaptor protein, p60. In turn, the membrane localization of PI3K allows it to phosphorylate phosphatidylinositol-4,5-P2 (PtdIns4••., 5••.P2), producing phosphatidylinositol-3,4,5-P3 (PtdIns3., 4••., 5••.P3). This second messenger then
Nutrient sensing through TOR
Given a cue to grow, such as insulin signaling, a cell needs a nutrient-rich environment to execute the command. How does a cell sense its environment? One proposed mechanism involves the target of rapamycin, TOR. TOR was first identified in yeast as a mediator of protein synthesis in response to nutrients (recently reviewed in [15]) and has been shown to regulate translation, ribosome biogenesis and uptake of amino acids. The first genetic analyses of TOR in a multicellular animal were
Other signaling pathways? Tuberous sclerosis
Tuberous sclerosis is a dominant genetic disorder in humans that causes a variety of benign tumors, some of which contain giant cells [23]. Two human genes have been identified that each account for approximately half the incidence of inherited disease [24]. TSC1 encodes a protein called hamartin, which appears to be a transmembrane protein and TSC2 encodes a protein called tuberin, which contains a region homologous to the GTPase-activating protein domain for Rap1. The two proteins can bind
Transcriptional regulation of growth by Myc
Myc proteins are members of the basic-helix-loop-helix-zipper class of transcription factors and are deregulated in several human cancers (reviewed in Nesbit et al. [29]). c-Myc expression is quickly induced in response to many mitogens but the promoter elements directing induction are not well characterized [30]. Numerous reports have indicated that Myc family members activate transcription of genes involved in protein synthesis and cellular metabolism 31., 32., 33.. These functions correlate
rRNA level regulation through Brat/Ncl-1
Brat was originally identified as a growth suppressor of the larval brain of Drosophila, with mutant brains growing up to eightfold larger than normal [43]. Loss of brat also conferred metastatic potential upon tissues transplanted into wildtype host flies [44]. Work on the Caenorhabditis elegans homologue, Ncl-1 demonstrated that ncl1?/? worms were larger, consisting of larger cells with enlarged nucleoli [45]. Recently, Brat has been characterized as a regulator of cell growth and rRNA
Conclusions
In the past couple of years, several determinants of cell size have been identified. Alteration of cell size by genetic manipulation of these determinants can manifest as disease 9••., 11••., 12••., 20••.. In multicellular systems, levels of growth factors, such as insulin, seem to be limiting for cell growth, even under optimal nutrient conditions (Fig. 3). Coordination between growth factors and nutrients was nicely established recently by Rathmell et al. [49••]. Their work demonstrated that
Update
Since submission of this review, three new papers of interest have been published 58., 59., 60.. The first of these studies [58] shows that continued cell growth upon cell-cycle arrest in tissue culture requires the activity of TOR and its downstream effectors, S6K and 4EBP. Perhaps using cell size as a readout of TOR activity in combination with defined tissue culture media could help elucidate nutrient-sensing pathways in mammalian cells. The two other publications identify new components of
Acknowledgements
We thank D Prober, S Grewal and L Johnston for critical reading of the manuscript, thoughtful discussions and helpful suggestions.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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