The years following the discovery of cyclin by Tim Hunt were filled with an abundance of discoveries relating to the cell cycle and its molecular processes.
Joan Ruderman, in collaboration with Katherine Swenson and Kevin Farrell, cloned the DNA coding for cyclin A from clam oocytes in 1986. They then created cyclin A mRNA in the lab and administered it to frog (Xenopus) oocytes which had been arrested at the border between gap 2 and meiosis I (Swenson, 1986: 861). The mRNA was translated by the frog oocytes and the resulting cyclin pushed the frog oocytes into meiosis. That indicated that cyclin A has some part in driving cells into meiosis.
Following his own work, Hunt began looking for ways to clone cyclin as well. With the ability to clone cyclin, and synthesize it in the lab, research with cyclin would expand dramatically. Hunt worked with molecular biologists Jeremy Minshull to clone cyclin B found in frog embryos (Jackson, 2008: 200). Once they had cloned cyclin B, they compared the DNA sequence of the cyclin A cloned by Ruderman and the cyclin B cloned by Hunt and Minshull and found that a particular part of the genetic code was conserved across both cyclins. That part was named the cyclin box (Jackson, 2008: 200).
At that point, in the late 1980s, it was yet unclear to researchers which was the major driver of mitosis - MPF or cyclin - though it was clear that both cyclin and MPF played a large role in the cell cycle. In particular, researchers did not know if it was the degradation of cyclin that caused a cell to exit mitosis or the degradation of MPF. In 1989, however, MBL researchers Marc Kirschner and Andrew Murray helped to answer that question. Using the cloned cyclin B from Hunt’s research, Murray and Kirschner showed that it was the degradation of cyclin that pushed the cell out of mitosis and that cyclin was the only required protein to cause a cell to enter into mitosis. That cemented cyclin’s role in the cell cycle, particularly as the main driver of mitosis (Pulverer, 2002).
Though cell cycle research had progressed significantly since Thomas Boveri’s work in 1902, many questions remained regarding the functioning of cyclin and its role in the cell cycle, such as the genetics behind cyclins and their functioning, and how cyclins are broken down in the cell in order to allow the cell to leave mitosis. Both of those questions were partially answered in the three years following Kirschner and Murray’s work.
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.