Whether or not cells enter the cell cycle is influenced by extracellular as well as intracellular signals. Unicellular organisms such as yeasts, for example, enter the cell cycle only when they have reached an appropriate size, known as the critical cell size. This critical size, in turn, is controlled by nutrients available in the environment. This coordination between cell size and cell cycle entry will be discussed in Section 19.7. Here we restrict our discussion to the fact that G₁ cyclin synthesis is responsive to the rate of protein synthesis, which is in turn controlled by pathways that are regulated by nutrients in the environment. This link between the macromolecule biosynthesis machinery and the cell cycle machinery is best understood in budding yeast. In this organism, the G₁ cyclin transcript CLN3 contains a short upstream open reading frame that inhibits translation initiation when nutrients are limited. This inhibition is diminished when nutrients are in abundance. In the presence of sufficient nutrients, the TOR signaling pathway, which senses nutrients and growth factor signals, is active and stimulates translational activity (see Figure 10-32). Since Cln3 is a highly unstable protein, its concentration fluctuates with the translation rate of its mRNA. Consequently, the amount and activity of Cln3-CDK complexes, which depend on the concentration of Cln3 protein, are regulated by nutrient levels.

In multicellular organisms, cells are surrounded by nutrients, and as such, nutrients do not usually limit the rate of cell proliferation. Rather, cell proliferation is controlled by the presence of growth-promoting factors (mitogens) and growth-inhibiting factors (anti-mitogens) in the cell surroundings. Addition of mitogens to G₀-arrested mammalian cells induces—as discussed in Chapter 16—receptor tyrosine kinase–linked signal transduction pathways that initiate signal transduction cascades that ultimately influence transcription and cell cycle control. They do so in multiple ways.

Mitogens activate the transcription of multiple genes. Most of these genes fall into one of two classes—early response or delayed response genes—depending on how soon their encoded mRNAs appear. Transcription of early response genes is induced within a few minutes after addition of growth factors by signal transduction cascades that activate preexisting transcription factors in the cytosol or nucleus (see Chapter 16). Many of the early response genes encode transcription factors, such as c-Fos and c-Jun, that stimulate transcription of the delayed response genes. The early response transcription factor Myc induces the transcription of G₁ cyclin and CDK genes. In addition to being controlled by transcription, G₁ CDKs are regulated by CKIs. The CKI p15INK4b is a potent CDK inhibitor. In some tissues, mitogens inhibit the production of this CKI by inhibiting its transcription.

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Cell proliferation in many tissues is regulated not only by proliferation-promoting mitogens, but also by anti-mitogens, which prevent entry into the cell cycle. Similarly, during differentiation, cells cease to divide and enter G₀. Some differentiated cells (e.g., fibroblasts and lymphocytes) can be stimulated to re-enter the cell cycle and replicate. Many postmitotic differentiated cells, however, never re-enter the cell cycle to replicate again. Anti-mitogens and differentiation pathways prevent the accumulation of G₁ CDKs. They antagonize the production of G₁ cyclins and induce the production of CKIs. Transforming growth factor β (TGF-β) is an important anti-mitogen. This hormone induces a signaling cascade that brings about G₁ arrest by inducing the expression of p15INK4b. As we will see in Chapter 24, the signaling pathways that regulate G₁ CDKs are found mutated in many human cancers.