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Pr. Liam HOLT / Control and consequences of the physical properties of cells
1 mars 2019 @ 11:00 - 13:00
The talk at a glance
Tens of thousands of biochemical reactions occur simultaneously in the cell. Small molecules are channeled through metabolic pathways at blistering speed. Giant complexes assemble to orchestrate transcription and translation. ATP fuels the active transport of organelles along microtubules, and actin networks drive membrane remodeling and agitate the cytoplasm. All of this occurs within a complex, crowded cell interior. This extreme physical environment is both essential for life, and a potential liability. We found that if cells become too dilute, they senesce and die. On the other hand, if they become too crowded, they cannot grow. Therefore, it is crucial to maintain homeostatic crowding by balancing biomass production and cell volume. We found that the central growth regulator, mTORC1, is a crucial regulator of crowding. When mTORC1 is active, the production of millions of ribosomes crowds the cytoplasm. When mTORC1 is inactive, crowding is decreased through autophagy. We also found that mechanical compression increases crowding. Both mTORC1 signaling and the mechanical environment are frequently perturbed in cancer. We propose that changes in the physical properties of the cell interior through compression and dysregulation of growth pathways play a crucial role in cancer cell biology.
A few publications on the subject
- Holt LJ, Krutchinsky, AN, Morgan, DO Positive Feedback Sharpens the Anaphase Switch. (2008) Nature, Jun 15, 454(7202):353-7 PMID: 18552837
- Holt, LJ, Tuch, BB, Villén, J, Johnson, AD, Gygi, SP & Morgan, DO (2009) Global analysis of Cdk1 substrate phosphoryation sites provides insights into evolution Science, 2009 Sep 25;325(5948):16 PMID: 19779198
- Howard, C., Hanson-Smith, V., Kennedy, K.J., Miller, C.J., Lou, H.J., Johnson, A.D., Turk, B., and Holt, L.J. Ancestral resurrection reveals evolutionary mechanisms of kinase plasticity. Elife 3. (2014).
- Delarue M, Poterewicz G, Hoxha O, Choi J, Yoo W, Kayser J, Holt LJ*, and Hallatschek O* (2017) The SCWISh network is essential for survival under mechanical pressure. PNAS, Dec 19;114(51) doi: 10.1073/pnas.1711204114 PMID: 29187529 * co-corresponding author
- Delarue, M., Brittingham G, Pfeffer S, Surovtsev I, Kennedy KJ, Pinglay S, Gutierrez I, Schaffer M, Chung J, Plizko J, Groves JT, Jacobs-Wagner C, Engel BD, and Holt LJ (2018) mTORC1 controls phase separation and the biophysical properties of the cytoplasm by tuning crowding (2018) Cell, Jul 12, 174(2):338-349 doi: 10.1016/j.cell.2018.05.042 PMID: 29937223
- Neurohr, G.E., Terry, R.L., Lengefeld, J., Bonney, M., Brittingham, G.P., Holt, L.J., and Amon, A. Excessive cell growth causes cytoplasm dilution and contributes to senescence. Cell (in press, 2019).