Joining the complex: Cyclin-dependent kinase inhibitory proteins and the cell cycle

Abstract

Matthias Peter and Ira Herskowitz Department of Biochemistry and Biophysics University of California, San Francisco San Francisco, California 94143-0448 Progression of eukaryotic cells through major cell cycle transitions is mediated by sequential assembly and activa- tion of key regulators, the cyclindependent kinases (CDKs) (Nasmyth, 1993). Checkpoint controls are super- imposed and ensure correct cell cycle transitions by moni- toring the execution of specific events (such as DNA repli- cation or spindle assembly) and coupling them to further progression. This intrinsic cell. cycle machinery is con- trolled by external signals such as growth factors and anti- mitogens to integrate cell division with environmental and developmental stimuli. Elucidating the regulation of CDKs is not only important for studying the cell cycle but may also contribute to understanding cancer. Active CDKs are comprised of a catalytic subunit, typi- cally of 34 kDa, and a regulatory subunit called a cyclin (Figure 1A). In budding and fission yeasts, single catalytic subunits are sufficient to drive the cell cycle, whereas in multicellular eukatyotes several structurally related but distinct catalytic subunits are involved. Different cyclin subunits are required at different phases in the cell cycle: Gl cyclins for the GllS transition, S phase cyclins for progression through S phase, and G2 or mitotic cyclins for entry into mitosis (Nasmyth, 1993). Recent studies have converged to identify an additional regulatory subunit for the CDKs, a protein that binds to the CDK-cyclin complex and inhibits its activity. These proteins are termed CDK inhibitory proteins (CKls). Most known CKls are involved in putting a brake on the cetl cycle: some play a role in response to extracellular signals, whereas others appear to function in intrinsic steps of the cell cycle. The purpose of this minireview is to describe CKls and place their function into the context of cell cycle regulation. Regulation of CDKs Activation of a CDK requires association of a cyclin and a catalytic subunit that is both phosphorylated on a con- served Thr residue and dephosphorylated on aTyr residue (Figure 1A; Nasmyth, 1993). The activated CDK can be inactivated in several different ways: cyclin levels can be reduced by turning down their transcription or by degrada- tion of the protein itself, the catalytic subunit can be de- phosphorylated at the activating Thr residue, or the cata- lytic subunit can be inhibited by phosphorylation of the Tyr residue. In contrast with these mechanisms, CKls function in a distinct manner (Figure 1 B) and satisfy the following crite- ria. First, aCKl associates in vivo with the catalytic subunit, the cyclin, or the CDK complex. Second, a CKI binds to a CDK complex in vitro and inhibits its activity toward exog- enous substrates, interferes with activation of the CDK, or both. Third, a CKI does not covalently modify either the cyclin or catalytic subunit.