Sci. STKE, 5 February 2002
Cell Cycle Checkpoints Chfr Ubiquitinates Plk1
Controlled degradation is in large measure the driving force that directs the cell cycle forward. Two ubiquitin ligases known to act during cell-cycle progression are the Skp1/cullin/F-box (SCF) ligase that controls the G1-to-S transition and the anaphase-promoting complex (APC) that controls exit from mitosis. Kang et al. show that Chfr (previously determined to be part of the G2-to-M checkpoint) is also a member of the ring finger family of ubiquitin ligases. Recombinant Chfr autoubiquitinated when incubated with the E2 ubiquitin-conjugating enzymes Ubc4, Ubc5A, and Ubc5B. In a Xenopus extract cell cycle assay system, addition of Chfr reduced the rate of activation of the kinase Cdc2 by prolonging phosphorylation of Cdc2 at the inhibitory site Tyr15 and delayed entry into mitosis. Chfr did not alter progression of mitosis once it had been initiated, suggesting that Chfr specifically regulated the G2-to-M transition. Inhibitors of proteasomal degradation did not interfere with mitotic progression in the absence of added Chfr, suggesting that Chfr acts a checkpoint regulator. In vitro assays showed that Chfr ubiquitinated Polo-like kinase 1 (Plk1) (and the Xenopus homolog Plx1) and promoted its degradation, which prevented the phosphorylation of the phosphatase Cdc25 and the kinase Wee, which in turn prolongs Cdc2 phosphorylation, inhibiting the transition into mitosis. Thus, there is now a third ubiquitin ligase Chfr that is important for regulating the cell cycle in response to agents that activate the G2 checkpoint.
D. Kang, J. Chen, J. Wong, G. Fang, The checkpoint protein Chfr is a ligase that ubiquitinates plk1 and inhibits Cdc2 at the G2 to M transition. J. Cell Biol. 156, 249-259 (2002). [Abstract] [Full Text]
Citation: Chfr Ubiquitinates Plk1. Sci. STKE 2002, tw57 (2002).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882