licensing centrosome duplication
TRANSCRIPT
Engulfed by CED-5WU, Y-C. and HORVITZ, H. R. (1998)
C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180
Nature 392, 501–504
Studies of proteins in nematodes have contributed signifi-cantly to the understanding of complex events, such asapoptosis, in vertebrates. In this elegant paper, Wu andHorwitz study the process of cell-corpse engulfment follow-ing apoptosis. Previous studies have indicated the involve-ment of at least six genes, named ced (for cell death ab-normal), in this process.
Nematodes deficient in ced-5 cannot engulf cell corpsesfollowing apoptosis and, in addition, are defective in themigration of a subset of cells. Cloning of the ced-5 geneand cDNA revealed that the deduced protein shows iden-tity with human protein DOCK180, implicated in integrin-mediated cell signalling and cell movement. Furthermore,both proteins show similarity to the Drosophila protein myo-blast city (MBC), involved in myoblast fusion and migrationof epithelial cells. The authors name this new family of pro-teins ‘CDM’ (for CED-5, DOCK180 and MBC) and proposethat these proteins all function to mediate extension of cellsurfaces. To test whether CED-5 and DOCK180 are relatedfunctionally, DOCK180 was expressed under the controlof a heatshock promoter in ced-5 nematode mutants, andthis indeed rescued part of the phenotype.
These results are highly interesting and shed new light ona step in the apoptotic response as well as in the complexmechanism of cell migration. Since only the migration ofa subset of cells is affected in ced-5 mutants, and syncytiaformation is left unaffected, it will be interesting to deter-mine whether similar proteins are involved in the migrationof other cell types as well as in cell-fusion events.
Licensing centrosomeduplication
HINCHCLIFFE, E. H., CASSELS, G. O., RIEDER, C. L. and SLUDER, G. (1998)
The coordination of centrosome reproduction withnuclear events of the cell cycle in the sea urchin zygote
J. Cell Biol. 140, 1417–1426
The centrioles are the fundamental building blocks of thecentrosome and are delivered to the egg upon fertilization.Two centrosomes are present in normal mitotic spindles.Failure to regulate centrosome number leads to multipolarspindles and, consequently, lethal erratic distribution of thechromosomes at cell division. Previous studies had indi-cated that centrosome number is regulated independentlyfrom the nuclear cycle. But what determines that centro-somes only duplicate once per cell cycle? Hinchcliffe et al.fertilized sea urchin eggs (zygotes) to address this question.Continuous centrosome duplication was observed whenS phase was prolonged by inhibition of DNA polymerase.Duplication was not affected by Cdk1–cyclin-B kinaseactivity (that, in this system, stably rises to supra-mitotic
levels when DNA duplication is inhibited). By contrast,mitotic arrest caused failure to duplicate the centrosome,although anaphase still occurred.
In accord with previous findings, multiple centrosomeduplication occurred if protein translation was blocked atfertilization, a condition that also blocks Cdk1–cyclin-B acti-vation. Thus, regulation of centrosome duplication occursindependently of Cdk1–cyclin-B activity and of the proteo-lytic events occurring during anaphase. Remarkably, if inhibi-tors of protein translation were applied during prophase ofthe first cell cycle (rather than at fertilization), the zygotesarrested in the second cell cycle and subsequently dupli-cated their centrosome only once over an eight-hour period(five cell cycles). Analysis of the arrests showed that zygotestreated with inhibitors of translation at fertilization werearrested in active S phase (verified by re-fertilizing zygotesto monitor active DNA replication by BrdU incorporation),whereas no DNA replication occurred in those arrestedduring the second cell cycle (G1 equivalent). Thus, genuineS-phase arrest is apparently necessary and sufficient to sup-port continuous centrosome duplication.
Interestingly, during S-phase arrest, the time for centro-some re-duplication was up to three times longer than onecomplete cell cycle (this also holds true for somatic cells).A slow S-phase-regulated clock might assure that centro-somes duplicate only once during the faster cell cycle. More-over, during a normal cell cycle, the previous S phasemight prime the centrioles/centrosome, ‘licensing’ themto duplicate only once during the next cell cycle.
A destructive role for thePolo-like kinases
DESCOMBES, P. and NIGG, E. A. (1998) The polo-like kinase Plx1 is required for M phase exit anddestruction of mitotic regulators in Xenopus egg extracts
EMBO J. 17, 1328–1335
KOTANI, S. et al. (1998)PKA and MPF-activated Polo-like kinase regulate
Anaphase-Promoting Complex activity and mitosis progression
Mol. Cell 1, 371–380
SHIRAYAMA, M., ZACHARIAE, W., CIOSK, R. and NASMYTH, K. (1998)
The Polo-like kinase Cdc5p and the WD-repeat proteinCdc20p/fizzy are regulators and substrates of the
anaphase promoting complex in Saccharomyces cerevisiaeEMBO J. 17, 1336–1349
The anaphase-promoting complex/cyclosome (APC/C) is aubiquitin–protein ligase complex required for the destruc-tion of anaphase inhibitors and the mitotic cyclins. TheAPC/C is activated in mitosis and inactivated during inter-phase, suggesting that it plays a major role in determiningthe timing of substrate degradation, but little is knownabout how the activity of the APC/C is regulated. Thesepapers provide evidence that the Polo-like kinases (PLKs),a family of cell-cycle regulators implicated in multipleaspects of mitotic progression, activate the APC/C to pro-mote the destruction of cyclin B and exit from mitosis.
HEA
DLI
NES
222 trends in CELL BIOLOGY (Vol. 8) June 1998
This month’sheadlines werecontributed by
Søren Andersen,Donald Gullberg
andFiona Townsley.