Roberts, SA; (2013) Mechanisms of Cell Growth. Doctoral thesis , UCL (University College London).

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Abstract

Cell growth, the addition of mass and volume, is required for the development and homeostasis of all organisms. In mammalian cells, cell growth and size homeostasis usually requires an instructive signal in the form of a growth factor with loss of this signal resulting in cell atrophy. The primary Schwann cell has proven a powerful system to study cell growth in vitro – underlining the requirement of growth factors for mammalian cells biogenesis. Using this system, IGF-1 was identified as a Schwann cell growth factor that drives cell volume addition. In contrast, NRG-1 has no effect on Schwann cell volume, but does drive mitochondrial biogenesis - highlighting that cell growth can be non-uniform, diverging from the simple coordinate addition of volume and organelles. In this thesis, I demonstrate that the addition of mass and volume can be uncoupled during cell growth. IGF-1 drives coordinate addition of cell mass and volume, whereas sustained Raf/MEK/ERK activation drives addition of protein mass and specific organelles in the absence of an increase in cell volume. Furthermore, the addition of volume can be uncoupled from mass accumulation, downstream of IGF-1. This demonstrates that factors other than protein mass limit volume addition. To investigate the regulation of cell volume I took two approaches: Firstly, a cellular approach - comparing plasma membrane dynamics in growing and growth factor-starved cells. I show that membrane turnover is extremely fast with the whole membrane internalised ~ three times an hour. Moreover, this rapid and ATP-dependent rate is maintained in starved, autophagic cells - indicating that it is an essential cellular process. The speed of membrane turnover however, precluded using this approach to identify how cells deliver membrane to the cell surface to drive plasma membrane expansion. Secondly, a biochemical approach - to identify important signalling pathways. I identify a critical role for de novo lipogenesis for both the addition and maintenance of cell volume and SREBP-2 as an essential transcription factor mediating this process.

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