Sci. STKE, 25 September 2001
Cell Cycle Degradation of Cyclin E and p27
Progression through the cell cycle is controlled by the activity of cyclin-dependent kinases (CDKs), which in turn are controlled by interactions with cyclins and CDK inhibitors. These cyclins and inhibitor proteins are regulated by scheduled degradation through a ubiquitin- and proteasome-dependent process (see Schwab and Tyers). Three groups (Koepp et al., Moberg et al., and Strohmaier et al.) identified the F-box protein responsible for targeting cyclin E to the E3 ubiquitin ligase, SCF complex, for degradation and another group (Malek et al.) has made progress understanding the degradation of the CDK inhibitor p27. In yeast, Drosophila, Caenorhabditis elegans, and humans, degradation of cyclin E, which stimulates S phase through interactions with Cdk2, is dependent on the E3 ubiquitin ligase, the SCF complex. Specific phosphorylation of cyclin E results in recognition by an F-box protein called Archipelago (ago) in flies, which has homologs called hCdc4 or Fbw7 in humans, Cdc4 in yeast, and Sel-10 in worms and mice. This interaction then promotes association with SCF, ubiquitination, and ultimately degradation of cyclin E. Mutations in hCdc4 are associated with human cancers.
The p27 story is a bit more complex. Using knock-in technology, Malek et al. found that expression of p27T187A (lacking the phosphorylation site thought to target p27 for degradation) produced viable, fertile mice with some alterations in cell proliferation. Analysis of the progression through the cell cycle of cells from various tissues in these knock-in mice showed that the mitogen-activated degradation of p27T187A in G1was not impaired, but that degradation in S phase was inhibited. Thus, two separate mechanisms appear to exist in different phases of the cell cycle for controlling degradation of p27. In the same manner as cyclin E, phosphorylation of p27 results in the interaction of p27 with an F-box protein, which then results in delivery of the p27 to the SCF complex for ubiquitination. Both the G1 and S phase degradation pathways require phosphorylation and recognition by the F-box protein Skp2. Thus, the pathways have many commonalities, but important distinctions, in terms of how p27 is initially phosphorylated for recognition for degradation.
M. Schwab, M. Tyers, Archipelago of destruction. Nature 413, 268-269 (2001). [Online Journal]
D. M. Koepp, L. K. Schaefer, X. Ye, K. Keyomarsi, C. Chu, J. W. Harper, S. J. Elledge, Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science 30 August 2001 (10.1126/science.1065203). [Abstract]
K. H. Moberg, D. W. Bell, D. C. R. Wahrer, D. A. Haber, E. K. Harihan, Archipelago regulates cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 413, 311-316 (2001). [Online Journal]
H. Strohmaier, C. H. Spruck, P. Kaiser, K.-A. Won, O. Sangfelt, S. I .Reed, Human F-box protein hDcd4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature 413, 316-322 (2001). [Online Journal]
N. P. Malek, H. Sundburg, S. McGrew, K. Nakayama, T. R. Kyriakidis, J. M. Roberts, A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Nature 413, 323-327 (2001). [Online Journal]
Citation: Degradation of Cyclin E and p27. Sci. STKE 2001, tw344 (2001).
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