In his Nobel Prize lecture, Hunt talked about how the same day he obtained the cyclin results from the sea urchin embryos, he met researcher John Gerhart at an MBL Friday evening lecture, an institutional tradition dating back to 1888. At that lecture, Gerhart shared the work he was doing with another MBL researcher, Marc Kirschner, and Mike Wu on maturation promoting factor (MPF), also known as mitosis promoting factor.
Researchers Yoshio Masui and Clement Markert identified MPF in 1971 in frog (Rana pipiens) oocytes. In frogs, the eggs are arrested at the gap 2 phase of mitosis and then, almost eight months later, are stimulated by progesterone to enter meiosis I. Meiosis is the cellular process by which sex cells, or gametes, are produced. The frog oocytes carry out meiosis I, but are arrested again before entering the meiosis II (the second half of meiosis) (Greaves, 2002). Once the eggs are fertilized, they continue through meiosis II. Masui and Markert found that if they removed the cytoplasm from eggs after exposing them to progesterone (thus ensuring that the eggs underwent mitosis and part of meiosis), and injected that cytoplasm into immature eggs that had yet to undergo mitosis, the eggs would mature and undergo mitosis and meiosis I (Masui, 1971).
Gerhart, Kirschner, and Wu worked with MPF in much the same way that Hunt and his team worked with cyclins. They studied the appearance and disappearance of the substance over the course of the cell cycle in frog (Xenopus laevis) oocytes (Gerhart, 1984). They found that MPF appears in high concentrations early in the cell cycle, but disappears during meiosis I before reappearing in meiosis II and then disappearing at the end of the cell cycle (Gerhart, 1984). From that, they concluded that MPF was closely tied to the oscillatory reactions involved in the cell cycle (Gerhart, 1984: 1252). The researchers also hypothesized that MPF acted only as an intermediary in the cell cycle. They suspected that another oscillating substance controlled the appearance and disappearance of MPF and that MPF subsequently directed the reactions that take place during the cell cycle (Gerhart, 1984: 1253).
When Hunt told Gerhart about the oscillating protein (cyclin) he had found in sea urchin embryos as they went through the cell cycle, Gerhart suggested that cyclin may be the protein which drove the production and destruction of MPF, which in turn drove the reactions of the cell cycle. It was determined many years later MPF is a combination molecule, made up of a cyclin and a cyclin dependent kinase. Without cyclin attached to the cyclin dependent kinase, the kinase cannot interact with the appropriate molecules in order to move mitosis along. MPF controls many aspects of the cell cycle and understanding its function can in part be attributed to the Friday evening lecture tradition at the MBL.
What are Cyclins?
- Branden, C. I. (1999). Introduction to Protein Structure. New York: Garland Science. - https://books.google.com/books?id=eUYWBAAAQBAJ&pg=PA107&lpg=PA107&dq=domain+structure+of+cyclins&source=bl&ots=Pz5XNBd3kZ&sig=n2O3Cw0Vr8GmvuV0y-KF6i0PfYw&hl=en&sa=X&ei=BQl3VfOqMu-HsQTY5YOwDQ&ved=0CGIQ6AEwCw#v=onepage&q=domain%20structure%20of%20cyclins&f=false
- Hershko, A. (1999). Mechanisms and regulation of the degradation of cyclin B. Philosophical Transactions of the Royal Society B: Biological Sciences, 354(1389), 1571-1576.
- Nobel Prize, 2001. http://www.nobelprize.org/nobel_prizes/medicine/laureates/2001/hunt-bio.html
Early Work with Cyclins
- Boveri, T. (1902). On multipolar mitosis as a means of analysis of the cell nucleus. Foundations of experimental embryology, 1964, 74-97.
- Franz, S. (2002). http://www.nature.com/celldivision/milestones/full/milestone02.html
- Greaves, S. (2002). http://www.nature.com/celldivision/milestones/full/milestone07.html
- Jackson, P.K. (2008). The Hunt for Cyclin. Cell, 134, 199-202
- MBL History Project. "Joan Ruderman Cyclin Research I." Filmed June 2015. MBL History Project Video, 5:58. Posted June 2015. http://history.archives.mbl.edu/node/16066.
- MBL History Project. "Joan Ruderman Cyclin Research II." Filmed June 2015. MBL History Project Video, 8:55. Posted June 2015. http://history.archives.mbl.edu/content/joan-ruderman-cyclin-research-ii-june-5-2015.
- Mitchell, A. (2002). http://www.nature.com/celldivision/milestones/full/milestone03.html
- Nath, D. (2002). http://www.nature.com/celldivision/milestones/full/milestone06.html
- Patterson, M. (2002). http://www.nature.com/celldivision/milestones/full/milestone05.html
- Rosenthal, E. T., Hunt, T., & Ruderman, J. V. (1980). Selective translation of mRNA controls the pattern of protein synthesis during early development of the surf clam, Spisula solidissima. Cell, 20(2), 487-494.
- Surridge, C. (2002). http://www.nature.com/celldivision/milestones/full/milestone01.html
Tim Hunt and His Discovery of Cyclin
- Evans, T., Rosenthal, E. T., Youngblom, J., Distel, D., & Hunt, T. (1983). Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell, 33(2), 389-396.
- Gerhart, J., Wu, M., & Kirschner, M. (1984). Cell cycle dynamics of an M-phase-specific cytoplasmic factor in Xenopus laevis oocytes and eggs. The Journal of Cell Biology, 98(4), 1247-1255.
- Hunt, T. (2001, December 9). Tim Hunt Nobel Lecture Protein Synthesis, Proteolysis, and Cell Cycle Transitions." Nobelprize.org. Retrieved from: http://www.nobelprize.org/nobel_prizes/medicine/laureates/2001/hunt-lecture.html
- Hunt, T. (2004). The Discovery of Cyclin (I). Cell, S116, S63-S64.
- Jackson, P.K. (2008). The Hunt for Cyclin. Cell, 134, 199-202
- Masui, Yoshio, and Clement L. Markert. "Cytoplasmic control of nuclear behavior during meiotic maturation of frog oocytes." Journal of Experimental Zoology Part A: Ecological Genetics and Physiology 177, no. 2 (1971): 129-145.
- Pulverer, B. (2002). http://www.nature.com/celldivision/milestones/full/milestone12.html
- Swenson, K. I., Farrell, K. M., & Ruderman, J. V. (1986). The clam embryo protein cyclin A induces entry into M phase and the resumption of meiosis in Xenopus oocytes. Cell, 47(6), 861-870.
Cyclins and Genetics
- Ciechanover, A., Finley, D., & Varshavsky, A. (1984). Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85. Cell, 37(1), 57-66.
- Glotzer, M., Murray, A. W., & Kirschner, M. W. (1991). Cyclin is degraded by the ubiquitin pathway. Nature, 349(6305), 132-138.
- Goldstein, G., Scheid, M., Hammerling, U., Schlesinger, D. H., Niall, H. D., & Boyse, E. A. (1975). Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. Proceedings of the National Academy of Sciences, 72(1), 11-15.
- Gould, K. L. & Nurse, P. (1991). Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature 342, 39-45.
- Greenwood, E. (2002). http://www.nature.com/celldivision/milestones/full/milestone09.html
- Hartwell, L. H., Culotti, J., Pringle, J. R., & Reid, B. J. (1974). Genetic control of the cell division cycle in yeast. Science, 183(4120), 46-51.
- Hershko, A. (1991). The ubiquitin pathway for protein degradation. Trends in biochemical sciences, 16, 265-268.
- Hershko, A. (1999). Mechanisms and regulation of the degradation of cyclin B. Philosophical Transactions of the Royal Society B: Biological Sciences, 354(1389), 1571-1576.
- Nature. (2004). A prize for protein degradation. Nature Cell Biology, 6(1011), doi:10.1038/ncb1104-1011.
- Nobel Prize 2001 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2001/
- Nobel Prize 2004 http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2004/ ; http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2004/hershko-bio.html
- Nurse, P. (1975). Genetic control of cell size at cell division in yeast. Nature, 256, 547-551.
- Nurse, P., & Thuriaux, P. (1980). Regulatory genes controlling mitosis in the fission yeast Schizosaccharomyces pombe. Genetics, 96(3), 627-637.
- Patterson, M. (2002). http://www.nature.com/celldivision/milestones/full/milestone05.html
- Russell, P. & Nurse, P. (1986). cdc25+ functions as an inducer in the mitotic control of fission yeast. Cell 45, 145-153.
- Schoenheimer, R. (1942). The Dynamic State of Body Constitutents. Cambridge: Harvard University Press.
- Varshavsky, A. (2006). The early history of the ubiquitin field. Protein science, 15(3), 647-654.