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13.2 Cell Cycle Regulation Factors: Cyclin-CDK Complex

Given that the sequence of cell cycle events from the M phase to the G1 phase, S phase, and G2 phase is universal, the progression mechanism is, needless to say, extremely important to living things. What therefore is the mechanism that causes the cell cycle to progress? One hypothesis is that regulators are involved in the control of cell cycle progression; they activate each phase to complete the appropriate step at the appropriate time. Another idea is that the progression of one phase directly affects the progression to the next phase, as in a line of dominos toppling over. The results of numerous studies support the former idea. It has gradually been elucidated that regulatory factors called cell cycle engines play a leading role in executing the progression of each phase in the cell cycle.

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13.2.1

Cell cycle engine

Cyclin-CDK (cyclin-dependent protein kinase) complexes play a central role in cell cycle progression (Figure 13-5). The function of cyclin-CDKs is to run the cell cycle smoothly, and these are therefore called “cell cycle engines.” Cyclins are proteins that vary in quantity throughout the cell cycle. The cyclins are expressed between the G1 and S phases, during the S phase, and between the G2 and M phases, known as the G1/S-phase cyclin, the S-phase cyclin, and the G2/M-phase cyclin, respectively. Each cyclin is rapidly synthesized during a specific phase of the cell cycle and is again promptly broken down after it serves its purpose. They are broken down not only because they are no longer needed, but because the breakdown is required for the cell cycle to transition to the next step. Meanwhile, the CDKs need to be synthesized de novo when cell proliferation starts from the G0 phase. Once the cell cycle starts, some types of CDK are broken down during a specific phase of the cell cycle, whereas others are not. When the cyclins and CDKs that are expressed in a specific phase are bonded and activated, they phosphorylate the specific serine and threonine residues of a target protein. The phosphorylated target protein executes the events occurring in the respective phases of the cell cycle.

Specifically, there are several types of G1/S-phase cyclins and G1/S-phase CDKs. Cyclin D-CDK4/6 complex and the cyclin E-CDK2 complex are representative examples of G1/S-phase cyclin-CDK complexes which function at the start of the S phase. G2/M-phase cyclin and G2/M-phase CDK (cyclin B-Cdc2 complex) function at the start of the M phase and induces nuclear membrane breakdown and chromosome formation when activated.

Figure 13-5 Cell cycle control by cyclin-CDK

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Early cell cycle research

The cyclin-CDK complex, which functions as the cell cycle engine, and their subunits were purified and identified for the first time by Manfred Lohka and James Maller in 1988; however, the first person who indicated their existence was Professor Yoshio Masui who was at that time conducting research at Yale University (presently, Professor Emeritus of University of Toronto, recipient of the Albert Lasker Award in 1998).

In 1969, Masui discovered that when the cytoplasm of frog oocytes treated with progesterone was injected into untreated immature oocytes, they matured. This maturation promoting factor was named “MPF,” which is derived from the initials letters. Eventually it was found that the factor exists and functions universally in eukaryotic cells during the M phase. It thus became known as the M-phase promoting factor, using the same initials, MPF. Purification and analysis of this MPF led to the identification of cyclin and protein phosphorylation enzyme CDK, whose amount and activity vary cyclically according to the progress of the cell cycle.

Around 1970, other pioneering studies on the cell cycle also followed, in addition to the discovery of MPF. For instance, Potu Rao and Robert Johnson (1970, Figure 13-4) suggested the presence of an S-phase inducer following cell fusion experiments using human cultured cells, and Leland Hatwell et al. (1970) isolated cell cycle mutants of budding yeast. The findings from these studies performed on different species led to the studies on cyclin-CDK, which exists universally in eukaryotes.

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13.2.2

Regulation of cyclin-CDK activity

The overall regulation of CDK activity is extremely complicated, but it can be summarized as illustrated in Figure 13-6. It is regulated by at least 4 molecular mechanisms: (1) binding to synthesized cyclin, (2) activation by phosphorylation, (3) suppression of activity by phosphorylation of the ATP-binding site and activation by dephosphorylation of the site, and (4) inhibition by cyclin-dependent kinase inhibitor (CKI, discussed later) binding. Indeed, cyclin-CDK activation is regulated by such diverse mechanisms because the cyclin-CDK plays a central role as the engine during the cell cycle. These diverse factors involved in molecular reactions such as protein synthesis and phosphorylation form an intricate mechanism that ensures DNA replication and cell division progress correctly in the cell cycle.

Figure 13-6 Mechanism of cyclin-CDK activity regulation

A) Four factors regulating CDK activation

B) Formation of cyclin-CDK complex and inactivation

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