Cell proliferation requires that cells multiply through the process of cell division and that individual cells grow through macromolecule biosynthesis. Cell growth and cell division are separate processes, but for cells to maintain a constant size as they multiply, cell growth and cell division must be tightly coordinated. For example, when nutrients are limited, cells reduce their growth rate, and cell division must be down-regulated accordingly. This type of coordination between cell growth and division is especially important in unicellular organisms that experience changes in nutrient availability as part of their natural life cycle. It is therefore not surprising that surveillance mechanisms exist that adjust cell division rate according to growth rate.

In budding yeast, cell growth and division are coordinated in G₁. In this stage of the cell cycle, the growth and division cycles are linked by the dependence of the activity of G₁ CDKs on cell growth. Which aspect of growth is linked to the cell cycle? Classic experiments using protein synthesis inhibitors indicate that growth rate, and hence cell cycle control by growth, is determined by protein synthesis. How protein synthesis controls G₁ CDK activity is an area of active investigation. The current thinking is that a “sizer” protein, whose abundance is tightly controlled by growth rate, accumulates in a specific compartment of the cell. When the sizer protein reaches a certain concentration, it serves as the signal that the appropriate cell size for cell cycle entry has been reached. This cell size is known as the critical cell size. In budding yeast, the G₁ cyclin Cln3 has been proposed as the sizer protein. Cln3 is subject to translational control and is highly unstable, which makes levels of this cyclin especially sensitive to protein synthesis rate. Cln3 localizes to the nucleus. It is thought that once the protein reaches a critical concentration in the nucleus, the process of cell cycle entry outlined in Figure 19-12 is set in motion. Importantly, size control is highly plastic: the length of G₁ and the critical cell size change with nutrient availability.

S. pombe grows as a rod-shaped cell that increases in length as it grows, then divides in the middle during mitosis to produce two daughter cells of equal size (see Figure 19-4). Unlike budding yeast and most metazoan cells, which grow primarily during G₁, this yeast does most of its growing during the G₂ phase of the cell cycle, and its entry into mitosis is carefully regulated in response to cell size. Recall that entry into mitosis is regulated by the protein kinase Wee1, which inhibits CDK1 by phosphorylating tyrosine 15 and threonine 14. When nutrients are limited, Wee1 phosphorylates CDK1; hence cells remain in G₂ until they reach the critical size for mitotic entry. Cdr2 appears to be the sizer protein in this yeast. Upon its synthesis, Cdr2 localizes in patches to the cell cortex in the middle of the cell. Cdr2 is an inhibitor of Wee1 (see Figure 19-18). As cells grow, the local concentration of Cdr2 in the middle of the cell rises, and inhibition of Wee1 occurs in the vicinity of Cdr2. Indeed, the centrosome, where CDK activation commences during G₂, localizes in the middle of the cell, close to the cell cortex.

Nutrients are usually not limiting in multicellular organisms. Instead, cell growth is controlled by growth factor signaling pathways such as the Ras, AMPK, and TOR pathways (see Chapters 10 and 16). These pathways also appear to be important for coordinating cell growth and division. Mutations in key components of growth factor signaling pathways, such as Myc, cause dramatic changes in cell size in Drosophila. Myc regulates the transcription of many genes important for macromolecule biosynthesis and also, more indirectly, regulates G₁ CDKs. Thus this transcription factor appears to integrate cell growth and division. However, the details of this coordination remain to be elucidated.