Culprits in the degradation of cyclin E apprehended

Critical events in the life of a cell require that the flux through particular regulatory pathways be abruptly and irreversibly altered in response to intracellular and extracellular signals. The central role played by reversible phosphorylation in controlling signaling pathways is well established, but in the last few years, ubiquitinmediated proteolysis has emerged as an equally important, and in some cases collaborative, partner in the control of regulatory processes in the cell. Ubiquitination, typically in the form of polyubiquitination, serves as a signal for destruction of the tagged protein by the 26S proteasome. Because the proteolytic event itself is very rapid, it is the process of ubiquitination that is rate limiting and highly regulated. Protein ubiquitination involves a cascade of ubiquitin transfer reactions and requires three components: E1, E2, and E3 (Hershko and Ciechanover 1998). In the first step, a ubiquitin-activating enzyme (E1) is charged with ubiquitin through a thiol–ester linkage. This ubiquitin is then transferred to one of a dozen or so ubiquitin conjugating enzymes (E2) also as a thiol–ester. The ubiquitin is finally transferred from the E2 to one or more lysine residues in the substrate with the aid of an E3 ubiquitin ligase. Multiple rounds of ubiquitin conjugation with the initial ubiquitin as the recipient lead to polyubiquitin chain formation. In essence, E3s function as substrate-specific adaptors by simultaneously binding substrate and the E2, although in some cases, E3s may also serve as an intermediate in the ubiquitin transfer process. Given that there are a large and diverse number of proteins whose abundance in the cell is controlled by ubiquitin-mediated proteolysis, how is sufficient diversity generated such that E3s selectively recognize only one or a few substrates? The answer to this question appears to be a superfamily of multicomponent E3s that dock substrates with a core ubiquitin-conjugating system via modular, substrate-specific adaptor proteins. The core-conjugating apparatus in several E3s includes a member of the Cullin/Cdc53 family of proteins first identified in budding yeast and Caenorhabditis elegans (Kipreos et al. 1996; Mathias et al. 1996; Willems et al. 1996). New work, including a recent paper in Genes and Development, implicates two distinct members of the Cullin family—Cul3 and Cul1—in the ubiquitin-mediated destruction of mammalian cyclin E, an activator of Cdk2 and an essential regulator of the G1/S transition (Singer et al. 1999; Dealy et al. 1999; Wang et al. 1999). The work reveals an unanticipated link between Cul3 and cell cycle control, and provides the first evidence that distinct Cullin complexes function in concert to control the levels of a single target protein. The requirement of Cul3 for embryonic development (Singer et al. 1999) provides yet another reminder of the importance of ubiquitin-mediated proteolysis in coordinating crucial events in the organism.