Author response: Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length

Animal cells come in many different sizes. In humans, for example, egg cells are thousands of times larger than sperm cells. Yet cells of any given type are often strikingly similar in size. The cells that line the surface of organs including the skin and kidneys are especially uniform; in fact a loss of size uniformity in certain tumors is a sign of malignancy. What kind of regulation could enable separate cells within a tissue to have the same size? One possibility is that each type of cell is programmed with a specific target size, and that a cell can sense if it strays from its target and compensate with longer or shorter periods of growth. Animal cells sensing their own size was first reported in the 1960s, and since then much research in this area has focused on “cell size checkpoints”. These mechanisms stop cells that are too small from progressing through the series of events that allow one cell to divide in two, which is known as the cell cycle. Supporting the existence of size checkpoints, studies in yeast have repeatedly shown that cells that start off smaller tend to grow for longer during stages of cell cycle named G1 and G2. Several researchers have proposed different mechanisms to explain how information about a cell’s starting size influences the length of its cell cycle to result in the negative correlation between these two factors. However, as yet no one had managed to find a way to break this negative correlation, which would greatly help scientists to confirm the actual mechanisms that cells use to sense their size. To address this, Liu, Ginzberg et al. first looked for chemicals that, when added to human cells, stopped cell size from being correlated with the time taken to complete a cell cycle. This search revealed that information about cell size is communicated to regulators of the cell cycle via a signaling pathway that involves an enzyme known as the p38 MAPK. Liu, Ginzberg et al. then showed that this specific pathway is activated in small but not large cells, where it slows the small cells’ progress through the cell cycle. As expected, inhibiting the p38 enzyme also broke down the relationship between time spent in G1 and cell size, and led to the human cells growing to a range of different sizes. These findings now pave the road to answering a fundamental question in cell biology: what is the elusive cell size sensor? Understanding how cells sense their size will open a window onto how quantitative information is programmed, sensed and communicated within living cells. These findings will shed also new light onto how cells specialize into cell types of different sizes, and what happens when cells lose the ability to sense or regulate their size in diseases like cancers.

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