During mitosis and meiosis the cell cycle is halted at certain time points — when animal cells await fertilization, for example. During the 1960s, scientists were furiously searching for the factor that mediated this process, but it wasn't until 1971 that Yoshio Masui and Clement Markert identified the maturation-promoting factor (MPF). It then took another 17 years before this factor was purified by Manfred Lohka, Marianne Hayes and James Maller.

	Image courtesy of Ellen Shibuya.

One of the main advances that allowed Masui and Markert to identify the mythical MPF was the use of frog oocytes to study the factors that induced mitosis and meiosis. Oocytes that develop in the frog Xenopus laevis arrest in the G2 stage of the cell cycle for up to 8 months, and are then induced by progesterone to enter meiosis I (the first cell division of meiosis). These oocytes proceed through meiosis I and arrest once more in the second meiotic metaphase. Only when the egg is fertilized is the nucleus released from arrest to complete meiosis.

Masui and Markert used these observations to study meiotic maturation in another frog, Rana pipiens. Maturation of these oocytes could be induced in vitro by the application of progesterone. Cytoplasm was removed from these mature, progesterone-treated oocytes and added at certain time points to immature arrested oocytes. The injected cytoplasm was able to induce maturation of immature oocytes 12 hours after being treated with progesterone, and was deemed to contain the elusive 'maturation-promoting factor'. Once MPF was identified in frogs, it was found in all species that researchers assayed (see further reading). Additional experiments in starfish oocytes by Marcel Dorée and colleagues clearly showed that MPF was a heterodimer consisting of cdc2 and cyclin B.

Early in 1984, the nature of MPF was still unknown. In this year, John Gerhart and colleagues examined the dynamics of MPF during mitosis and meiosis in Xenopus laevis eggs and oocytes. The authors extracted MPF from eggs and oocytes and determined that this factor appears early during the cell cycle and then rapidly disappears during the first meiotic cycle. MPF then appears during the second meiotic cycle and disappears when maturation arrests. Therefore, MPF activity cycles throughout meiosis.

This observation and the techniques developed in previous studies allowed Lohka and colleagues to purify MPF in 1988. Using ammonium sulphate precipitation and six chromatographic procedures, the authors purified MPF from unfertilized Xenopus oocytes. Once the preparation was purified, it could induce germinal-vesicle breakdown in Xenopus oocytes within 2 hours. The authors postulated that MPF was composed of two components, one of which contained kinase activity. Additional experiments in yeast showed the kinase subunit to be a catalytic cyclin-dependent kinase, whereas experiments in sea-urchin embryos identified the other protein as a cyclin (see further reading).

Work that followed these ground-breaking findings determined that MPF is also the key factor that regulates the initiation of mitosis in all eukaryotic cells, and is now referred to as the mitosis-promoting factor. It is interesting to think that, 30 years after the first paper mentioned MPF, most of the targets of this complex are still unknown.

Sarah Greaves, Senior Editor, Nature Cell Biology

References

	ORIGINAL RESEARCH PAPERS Masui, Y. & Markert, C. L. Cytoplasmic control of nuclear behavior during meiotic maturation of frog oocytes. J. Exp. Zool. 177, 129-145 (1971) | PubMed |
	Gerhart, J., Wu, M. & Kirschner, M. Cell cycle dynamics of an M-phase-specific cytoplasmic factor in Xenopus laevis oocytes and eggs. J. Cell Biol. 98, 1247-1255 (1984) | PubMed |
	Lohka, M. J., Hayes, M. K. & Maller, J. M. Purification of maturation-promoting factor, an intracellular regulator of early mitotic events. Proc. Natl Acad. Sci. USA 85, 3009-3013 (1988) | PubMed |
	FURTHER READING Arion, D., Meijer, L., Brizuela, L. & Beach, D. cdc2 is a component of the M phase specific histone H1 kinase: evidence for identity with MPF. Cell 55, 371-378 (1988) | PubMed |
	Draetta, G. et al. cdc2 protein kinase is complexed with both cyclin A and B: evidence for proteolytic inactivation of MPF. Cell 56, 829-838 (1989) | PubMed |
	Dunphy, W. G., Brizuela, L., Beach, D. & Newport, J. The Xenopus cdc2 protein is a component of MPF, a cytoplasmic regulator of mitosis. Cell 54, 423-431 (1988) | PubMed |
	Evans, T., Rosenthal E. T., Youngblom. J., Distel. D. & Hunt, T. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 33, 389-396 (1983) | PubMed |
	Gautier, J., Norbury, C., Lohka, M., Nurse, P. & Maller, J. Purified maturation-promoting factor contains the product of a Xenopus homolog of the fission yeast cell cycle control gene cdc2+. Cell 54, 433-439 (1988) | PubMed |
	Labbe, J. C., Lee, M. G., Nurse, P., Picard, A. & Doree, M. Activation at M-phase of a protein kinase encoded by a starfish homologue of the cell cycle control gene cdc2. Nature 335, 251-254 (1988) | PubMed |
	Labbe, J. C. et al. MPF from starfish oocytes at first meiotic metaphase is a heterodimer containing one molecule of cdc2 and one molecule of cyclin B. EMBO J 8, 3053-3058 (1989) | PubMed |
	Luca, F. C., Ruderman, J. & Hunt, T. The requirements for protein synthesis and degradation, and the control of destruction of cyclins A and B in the meiotic and mitotic cell cycles of the clam embryo. J. Cell Biol. 116, 707-724 (1992) | PubMed |
	Masui, Y. The elusive cytostatic factor in the animal egg. Nature Rev. Mol. Cell Biol. 1, 228-232 (2001) | PubMed | FREE ARTICLE |