The APC/C and SCF are both large, multisubunit complexes with some related components (see Figure 3–71), but they are regulated differently. APC/C activity changes during the cell cycle, primarily as a result of changes in its association with an activating subunit—either Cdc20 in mid-mitosis or Cdh1 from late mitosis through early G1. These subunits help the APC/C recognize its target proteins (Figure 17–15A). SCF activity depends on substrate-binding subunits called F-box proteins. Unlike APC/C activity, however, SCF activity is constant during the cell cycle. Ubiquitylation by SCF is controlled instead by changes in the phosphorylation state of its target proteins, as F-box subunits recognize only specifically phosphorylated proteins (Figure 17–15B).
In the simple cell cycles of early animal embryos, gene transcription does not occur. Cell-cycle control depends exclusively on post-transcriptional mechanisms that involve the regulation of Cdks and ubiquitin ligases and their target proteins. In the more complex cell cycles of most cell types, however, transcriptional control provides an important additional level of regulation. Changes in cyclin gene transcription, for example, help control cyclin levels in most cells.
A variety of methods discussed in Chapter 8 have been used to analyze changes in the expression of all genes in the genome as the cell progresses through the cell cycle. The results of these studies are surprising. In budding yeast, for example, about 10% of the genes encode mRNAs whose levels oscillate during the cell cycle. Some of these genes encode proteins with known cell-cycle functions, but the functions of many others are unknown.
The Cell-Cycle Control system Functions as a network of Biochemical switches
Table 17–2 summarizes some of the major components of the cell-cycle control system. These proteins are functionally linked to form a robust network, which operates essentially autonomously to activate a series of biochemical switches, each of which triggers a specific cell-cycle event.
When conditions for cell proliferation are right, various external and internal signals stimulate the activation of G1-Cdk, which in turn stimulates the expression of genes encoding G1/Sand S-cyclins (Figure 17–16). The resulting activation of G1/S-Cdk then drives progression through the Start transition. By mechanisms we discuss later, G1/S-Cdks unleash a wave of S-Cdk activity, which initiates (A) control of proteolysis by APC/C (B) control of proteolysis by SCF
Figure 17–15 The control of proteolysis by APC/C and SCF during the cell cycle. (a) The apC/C is activated in mitosis by association with Cdc20, which recognizes specific amino acid sequences on m-cyclin and other target proteins. With the help of two additional proteins called E1 and E2, the apC/C assembles polyubiquitin chains on the target protein. The polyubiquitylated target is then recognized and degraded in a proteasome. (B) The activity of the ubiquitin ligase sCF depends on substrate-binding subunits called F-box proteins, of which there are many different types. The phosphorylation of a target protein, such as the CkI shown, allows the target to be recognized by a specific F-box subunit.
chromosome duplication in S phase and also contributes to some early events of mitosis. M-Cdk activation then triggers progression through the G2/M transition and the events of early mitosis, leading to the alignment of sister-chromatid pairs at the equator of the mitotic spindle. Finally, the APC/C, together with its activator Cdc20, triggers the destruction of securin and cyclins, thereby unleashing sister-chromatid separation and segregation and the completion of mitosis. When mitosis is complete, multiple mechanisms collaborate to suppress Cdk activity, resulting in a stable G1 period. We are now ready to discuss these cell-cycle stages in more detail, starting with S phase.