Significance
For over a century, it has been known that the ratio of the nuclear and cytoplasm volumes (NC ratio), rather than the separate volumes, is constant among cells of many types of organisms. Changes of the NC ratio are associated with cancerous transformations, suggesting that the ratio has physiological importance. Notably, the dominant regulatory mechanism of the NC ratio has not been identified. Here, we use physical estimates of the forces implicated in nuclear volume determination and show that they are dominated by the osmotic pressure of actively transported proteins. Inspired by this, we formulate a minimal model for the cytoplasmic and nuclear volumes that predicts the NC ratio and the factors that modulate it, in agreement with published experiments.