Why Are Cells So Small?

Or, why are they one size, and not another?

One significant conundrum in biology is how cells know what size they are, and what size they are supposed to be. Bacteria are tiny, while eukaryotic cells are huge in comparison. And eukaryotic cells vary tremendously in size, from small yeast cells to peripheral nerves that span much of your body, even on to ostrich eggs. Outside of yeasts, not much is known about how these cells judge what size is right and when to divide. A recent paper proposed that the protein Rb plays an important role in setting cell size, at least for some eukaryotic cell types.

Rb is named for retinoblastoma, the form of cancer it is most directly responsible for, and is a well known gene. Many other cancers also have mutations in Rb, since it is what is called a "tumor suppressor gene". That is, it is the opposite of an oncogene. Rb interacts with hundreds of proteins in our cells, but its most important partner is transcription activator E2F1, an activator of cell cycle progression. Rb binds to and inhibits the activity of E2F1, (and a family of related proteins), halting cell division until some alteration takes place, like a regulatory phosphorylation that shuts Rb off, or an insufficient amount remaining in the cell.

The researchers took a clue from yeast, whose gene Whi5 accomplishes similar inhibition of the cell cycle as Rb, and is known to regulate the size of cells at division. So this work was not a big surprise. The interesting aspect is that Rb now has one more role, which logically integrates with its other known roles in the cell cycle. The authors used cells that over or under-express Rb to show that the copy number of Rb has a significant, if not overwhelming, effect on cell size. 

Amount of Rb correlates with the size of cell. The authors set up an inducible genetic construct to drive Rb expression, from zero to four times normal amounts.

So how do they imagine this mechanism working? Rb is a durable, stable protein, with a half-life almost twice as long (29 hours) as the cell division cycle in the conditions the experimenters used. Secondly, all Rb is pretty much in the nucleus, attached to DNA. So at cell division, roughly equal amounts necessarily partition to each daughter cell, even if their cell volumes are very different. Thereafter, each cell synthesizes Rb at a low rate, which does not keep up with cell growth, especially during the G1 phase of the cell cycle- that period prior to DNA replication and commitment to division. In fact, very little Rb is made in that period, allowing it to serve as a limiting factor through dilution as the cell grows. And when it is sufficiently dilute, it then contributes to the decision to have new cell cycle, by letting go of its repression of E2F1.

How several proteins accumulate during the cell cycle. Rb is shown in dark blue, and hardly accumulates at all in G1, the growth phase of the cell cycle before DNA replication (S phase) and division (M phase). For comparison, nuclear volume and a generic translation protein (EF1) rise monotonically with cell growth. Cdt1 is a key licensing factor for DNA replication. It accumulates during G1, and after the DNA replication origins fire, is destroyed by the end of S phase. Conversely, Geminin is a protein that binds to and represses Cdt1, preventing re-replication of DNA that has already replicated once. It accumulates during S phase and stays high until after division. After S phase, more Rb is made, partially catching up to the current cell size. 

That is the theory, at least, backed by pretty good evidence. But its effect is not proportional, and not uniform among cell types. There are clearly other controls over cell size in play- this is only one. Indeed, there are a couple of siblings of Rb (in a family termed "pocket proteins") which also regulate the cell cycle, and a vast network of other controls and stimuli that impinge on it. So finding even one regulator of this kind, and finding conditions where it has strong effects on cell size, is quite significant. As for the ultimate rationale of cell size in these or other instances, Rb regulation is only a mechanism that enforces logic that has been arrived at over evolutionary time, about the practical limits and ideal proportions of cells in, in this case, the human body, in response to various situations. Smaller cells have one virtue, that they are more easily disposable- such as the countless skin and gut epithelial cells that are sacrificed daily. Our long peripheral nerves are much more difficult to replace.

Conversely, Rb has many other roles in the cell, as suggested by the vast number of its interaction partners, diagrammed below by functional classification.

Functional classification of the many proteins that interact directly with Rb. It also has about 15 phosphorylation sites that can be regulated by various kinases.

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