. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM039565-23
Application #
7790673
Study Section
Special Emphasis Panel (ZRG1-NDT-K (01))
Program Officer
Deatherage, James F
Project Start
1988-02-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
23
Fiscal Year
2010
Total Cost
$515,585
Indirect Cost
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Hanley, Mariah L; Yoo, Tae Yeon; Sonnett, Matthew et al. (2017) Chromosomal passenger complex hydrodynamics suggests chaperoning of the inactive state by nucleoplasmin/nucleophosmin. Mol Biol Cell 28:1444-1456
Guild, Joshua; Ginzberg, Miriam B; Hueschen, Christina L et al. (2017) Increased lateral microtubule contact at the cell cortex is sufficient to drive mammalian spindle elongation. Mol Biol Cell 28:1975-1983
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:
Boke, Elvan; Mitchison, Timothy J (2017) The balbiani body and the concept of physiological amyloids. Cell Cycle 16:153-154
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
Mooney, Paul; Sulerud, Taylor; Pelletier, James F et al. (2017) Tau-based fluorescent protein fusions to visualize microtubules. Cytoskeleton (Hoboken) 74:221-232
Mitchison, Timothy J; Field, Christine M (2017) Spindle-to-Cortex Communication in Cleaving Frog Eggs. Cold Spring Harb Symp Quant Biol :
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
Groen, Aaron C; Mitchison, Timothy J (2016) Purification and Fluorescent Labeling of Tubulin from Xenopus laevis Egg Extracts. Methods Mol Biol 1413:35-45
Ishihara, Keisuke; Korolev, Kirill S; Mitchison, Timothy J (2016) Physical basis of large microtubule aster growth. Elife 5:

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