. When cells divide they build a transient structure called the mitotic spindle to separate their chromosomes into two equal groups. Spindle assembly is a fundamental and fascinating process. We will study the molecules required to build mitotic spindles, and how they generate structures and forces within spindles. Blocking spindle assembly is an effective way of killing cancer cells, and understanding basic mechanisms of spindle assembly will reveal targets for more effective anti-cancer drugs. In the last grant period, we discovered that an unusual molecule called poly(ADP-ribose) is an essential building block of spindles, and we hypothesize that it may be part of a mysterious """"""""spindle matrix"""""""" that helps physically organize spindles. We will look for proteins that bind to this molecule, and determine how it contributes to structures and forces within the spindle. The most studied components of spindles are microtubules, long filaments made of the protein tubulin, which grow and shrink rapidly and generate force on chromosomes. We will investigate the biochemical reactions that create new microtubules in the spindle. We will also use new microscopy methods to visualize how microtubules move within the spindle, and mathematical models to understand how the creation, movement and loss of microtubules generates the characteristic size and shape of spindles. Relevance Our studies will address major unresolved questions about how spindles self-organize to generate a stereotyped structure that nevertheless adjusts itself depending on circumstances, and how they perform their essential biological functions. These discoveries will have immediate relevance to the development of novel cancer drugs. ? ? ?
| Nguyen, P A; Field, C M; Mitchison, T J (2018) Prc1E and Kif4A control microtubule organization within and between large Xenopus egg asters. Mol Biol Cell 29:304-316 |
| Pineda, Javier J; Miller, Miles A; Song, Yuyu et al. (2018) Site occupancy calibration of taxane pharmacology in live cells and tissues. Proc Natl Acad Sci U S A 115:E11406-E11414 |
| Field, Christine M; Mitchison, Timothy J (2018) Assembly of Spindles and Asters in Xenopus Egg Extracts. Cold Spring Harb Protoc 2018:pdb.prot099796 |
| Liu, Ling; Su, Xiaoyang; Quinn 3rd, William J et al. (2018) Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. Cell Metab 27:1067-1080.e5 |
| Boke, Elvan; Mitchison, Timothy J (2017) The balbiani body and the concept of physiological amyloids. Cell Cycle 16:153-154 |
| Mooney, Paul; Sulerud, Taylor; Pelletier, James F et al. (2017) Tau-based fluorescent protein fusions to visualize microtubules. Cytoskeleton (Hoboken) 74:221-232 |
| Mitchison, T J; Pineda, J; Shi, J et al. (2017) Is inflammatory micronucleation the key to a successful anti-mitotic cancer drug? Open Biol 7: |
| Field, C M; Pelletier, J F; Mitchison, T J (2017) Xenopus extract approaches to studying microtubule organization and signaling in cytokinesis. Methods Cell Biol 137:395-435 |
| Presler, Marc; Van Itallie, Elizabeth; Klein, Allon M et al. (2017) Proteomics of phosphorylation and protein dynamics during fertilization and meiotic exit in the Xenopus egg. Proc Natl Acad Sci U S A 114:E10838-E10847 |
| Costigliola, Nancy; Ding, Liya; Burckhardt, Christoph J et al. (2017) Vimentin fibers orient traction stress. Proc Natl Acad Sci U S A 114:5195-5200 |
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