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ALTHOUGH mitotic cyclins are well-known substrates for ubiquitin-mediated proteolysis at the metaphase–anaphase transition1–4, their degradation is not essential for separation of sister chromatids5–8; several lines of evidence suggest that proteolysis of other protein(s) is required, however4,6,9–11. Here we report the anaphase-specific proteolysis of the Schizosaccharomyces pombe Cut2 protein, which is essential for sister-chromatid separation12,13. Cut2 is located in the nucleus, where it is concentrated along the short metaphase spindle. The rapid degradation of Cut2 at anaphase requires its amino-terminal region and the activity of Cut9 (ref. 14), a component of the 20S cyclosome/ anaphase-promoting complex (APC), which is necessary for cyclin destruction3,4,11. Expression of non-degradable Cut2 blocks sister-chromatid separation but not cell-cycle progression. This defect can be overcome by grafting the N terminus of cyclin B onto the truncated Cut2, demonstrating that the regulated proteolysis of Cut2 is essential for sister-chromatid separation.

Europe's future hinges on funding transdisciplinary scientific collaboration. But career paths, peer recognition, publication channels and the public funding of science are still mostly geared to maintain and reinforce disciplinarity.We do not properly understand the effects of technology on the evolution of the systems on which we all depend. To take on global challenges such as climate change, growing urbanization and loss of biodiversity, we need to build a new science community that will explore common themes in natural, artificial and social systems.The Santa Fe Institute in New Mexico, founded 25 years ago by scientists to create new sciences from combinations of the old, has changed science and technology by investigating how simple building blocks interact, from molecules to single cells to ecological systems to human communities. Singapore is developing a similar institute and so is Japan. They have caught on to the idea that today's world needs sciences recast for the future. They are investing in it. Europe is not — at least, not enough.The Institute Para Limes, in doesburg, the Netherlands, follows the Santa Fe model and symbolizes the quintessence of the European Union (EU): a community without boundaries, national or disciplinary. It is endorsed by scientists, by leaders of the national science academies, by some companies and by high-ranking EU officials. They recognize that such a community cannot be built from within universities organized along disciplinary lines, or from institutes that serve national interests.But this community is caught between two systems for funding research. In one, the EU pursues its goals through huge, bureaucratic Framework programmes — the seventh programme's budget is euro53.2 billion (US$72.4 billion) over seven years. Common interest is all, with no support for initiatives in individual member states. In the other system, member states use public money to pursue their own goals — justified, in their view, by their payment of the EU's annual fee.The yearly budget for the Institute Para Limes will be between euro6 million and euro10 million — too small on the EU scale to stimulate bureaucratic interest, but large enough on a national scale to be in competition with established institutes. Independent funding is urgently needed. We call on entrepreneurs, company executives, private foundations and visionary individuals for support.Only then can we build on the institute's early promise and deliver a better understanding of systems that humanity needs for adequate food, energy, water and health without causing damage to the environment.

Fertilization induces a transient increase in cytoplasmic Ca2+ concentration in animal eggs that releases them from cell cycle arrest in the second meiotic metaphase. In frog eggs, Ca2+ activates Ca2+/calmodulin-activated kinase, which inactivates cytostatic factor, allowing the anaphase-promoting factor to turn on and ubiquitinate cyclins and securin, which returns the cell cycle to interphase. Here we show that the calcium-activated protein phosphatase calcineurin is also important in this process. Calcineurin is transiently activated after adding Ca2+ to egg extracts, and inhibitors of calcineurin such as cyclosporin A (ref. 8) delay the destruction of cyclins, the global dephosphorylation of M-phase-specific phosphoproteins and the re-formation of a fully functional nuclear envelope. We found that a second wave of phosphatase activity directed at mitotic phosphoproteins appears after the spike of calcineurin activity. This activity disappeared the next time the extract entered M phase and reappeared at the end of mitosis. We surmise that inhibition of this second phosphatase activity is important in allowing cells to enter mitosis, and, conversely, that its activation is required for a timely return to interphase. Calcineurin is required to break the deep cell cycle arrest imposed by the Mos-MAP (mitogen-activated protein) kinase pathway, and we show that Fizzy/Cdc20, a key regulator of the anaphase-promoting factor, is an excellent substrate for this phosphatase.

Phosphorylation of the neurofilament proteins of high and medium relative molecular mass, as well as of the Alzheimer's tau protein, is thought to be catalysed by a protein kinase with Cdc2-like substrate specificity. We have purified a novel Cdc2-like kinase from bovine brain capable of phosphorylating both the neurofilament proteins and tau. The purified enzyme is a heterodimer of cyclin-dependent kinase 5 (Cdk5) and a novel regulatory subunit, p25 (ref. 8). When overexpressed and purified from Escherichia coli, p25 can activate Cdk5 in vitro. Unlike Cdk5, which is ubiquitously expressed in human tissue, the p25 transcript is expressed only in brain. A full-length complementary DNA clone showed that p25 is a truncated form of a larger protein precursor, p35, which seems to be the predominant form of the protein in crude brain extract. Cdk5/p35 is the first example of a Cdc2-like kinase with neuronal function.

THE cell cycles of early Xenopus embryos consist of a rapid succession of alternating S and M phases1. These cycles are controlled by the activity of a protein kinase complex (cdc2 kinase) which contains two subunits. One subunit is encoded by the frog homologue of the fission yeast cdc2+ gene, p34cdc2 (ref. 2) and the other is a cyclin3. The concentration of cyclins follows a sawtooth oscillation because they accumulate in interphase and are destroyed abruptly during mitosis3. The association of cyclin and p34cdc2 (refs 4–7) is not sufficient for activation of cdc2 kinase, however; dephosphorylation of key tyrosine and threonine residues of p34cdc2 is necessary to turn on its kinase activity8–11. The activity of cdc2 kinase is thus regulated by a combination of translational and post-translational mechanisms. The loss of cdc2 kinase activity at the end of mitosis depends on the destruction of the cyclin subunits3,4,12,13. It has been suggested that this destruction is induced by cdc2 kinase itself, thereby providing a negative feedback loop to terminate mitosis14,15. Here we report direct experimental evidence for this idea by showing that cyclin proteolysis can be triggered by adding cdc2 kinase to a cell-free extract of interphase Xenopus eggs.

In vertebrates, mature eggs are arrested at the second meiotic metaphase by the cytostatic factor (CSF), now known to be the c-mos proto-oncogene product (Mos). Fertilization or egg activation triggers a transient increase in the cytoplasmic free calcium and releases the meiotic arrest by inactivating maturation/mitosis-promoting factor (MPF). CSF or Mos, which is also inactivated by the calcium transient, seems to stabilize MPF in mature eggs and CSF-injected embryos. Thus, it was assumed that CSF inactivation is the primary cause of MPF inactivation on meiotic release. We have directly compared the degradation kinetics of CSF (Mos) and MPF during meiotic release, using the same batch of Xenopus eggs. We report here that, at the molecular level, cyclin subunits of MPF are degraded before Mos is degraded and, at the physiological level, that MPF activity is inactivated before CSF activity during activation of Xenopus eggs. These results, in conjunction with circumstantial evidence, support the novel view that a calcium transient on fertilization induces a CSF-independent pathway for MPF inactivation, whereas CSF inactivation during meiotic release serves only to allow the fertilized egg to enter mitosis.

Oogenesis. Developmental Biology: A Comprehensive Synthesis, Vol. 1. Edited by Leon W. Browder. Plenum: 1985. Pp.632. $75, £71.25.