Research Faculty

Address
630 West 168th Street
P&S 14-460
New York, NY 10032

Phone: 212-305-7914
Fax: 212-342-5459

ym2183@cumc.columbia.edu
Education and Training
Ph.D. 2000 The Ohio State University
Affiliations
Pathobiology
Yinghui Mao, Ph.D.
Associate Professor of Pathology and Cell Biology
Research Summary

Chromosome Segregation, the Mitotic Checkpoint, and Aneuploidy.

Accurate delivery of one copy of each chromosome is essential every time a cell duplicates, a process that takes place millions of times every day in every individual. Errors in this process cause misdistribution of chromosomes (aneuploidy), which early in development lead to lethal developmental defects and later are hallmarks of human tumor progression. The goal of the laboratory is to elucidate the principles of chromosome segregation and to identify and understand the roles of individual proteins involved. Our primary approach is to reconstruct the cell cycle in the test tube using a cell-free system derived from the African frog Xenopus laevis eggs. In addition, we are using mammalian cultured cells to identify and characterize the key factors important for chromosome segregation in mitosis.

Kinetochore microtubule attachment. The accurate segregation of chromosomes in mitosis requires the stable attachment of microtubules to kinetochores, the protein complex assembled at each centromere - a discrete locus on each chromosome. The details of this complex and dynamic process are poorly understood. We are evaluating the roles of kinetochore associated proteins and microtubule effectors, including motors, kinases, and microtubule associated proteins, in stable kinetochore microtubule attachment in Xenopus egg extracts and mammalian cultured cells, and developing in vitro reconstitution using purified components.

The mitotic checkpoint. Eukaryotic organisms have evolved a "mitotic checkpoint" to prevent premature advance to anaphase prior to successful attachment of every chromosomes to microtubules of the mitotic spindle. Various mitotic checkpoint proteins are recruited onto unattached kinetochores, where they generate a diffusible signal to prevent chromosome segregation. Current efforts, using a convergence of cell biology and biochemistry to determine the functional properties of kinetochore components (including BubR1, Bub3, Mad1, Mad2, and Cdc20), are underway to dissect this major cell cycle control mechanism that maintains genome integrity.

Anti-mitotic drugs. Cancer is above all else a disease of cell proliferation. Directly targeting the mitotic apparatus has been an effective approach that has been used for many years. However, most anti-mitotic drugs target microtubule - the major component of the mitotic spindle. Because these drugs, such as taxanes and vinca alkaloids, do not distinguish between microtubules involved in mitosis and those involved in cell motility, cell shape, and intracellular transport in neurons, they frequently associate with significant toxic side effects, including neuropathy, myelosuppression, and cardiomyopathy. It has recently been appreciated that other components of the mitotic spindle, that are only expressed in mitotically-active cells, can also be targeted to produce mitotic defects that lead to apoptotic cell death. In collaboration with the laboratory of Dr. Steven Rosenfeld, we are screening for inhibitors of mitotic motors, such as the mitotic kinesin Eg5.
Selected Publications

1. Rozier, L., Guo, Y., Peterson, S., Sato, M., Baer, R., Gautier J., and Mao, Y. The MRN-CtIP pathway is required for metaphase chromosome alignment. Molecular Cell 2013, 49:1097-1107

2. Guo, Y., Kim, C., Ahmad, S., Zhang, J., and Mao, Y. CENP-E-dependent BubR1 auto-phosphorylation enhances chromosome alignment and the mitotic checkpoint. The Journal of Cell Biology 2012, 198: 205-217.

3. Mao, Y. FORMIN a link between kinetochores and microtubule ends. Trends in Cell Biology 2011, 211: 625-629. Opinion article.

4. Cheng, L, Zhang, J., Ahmad, S., Rozier, L., Yu, H., Deng, H., and Mao, Y. Aurora B regulates formin mDia3 in achieving metaphase chromosome alignment. Developmental Cell 2011, 20: 342-352.

5. Mao, Y., Varma, D., and Vallee, R.B. Emerging functions of force-producing kinetochore motors. Cell Cycle 2010, 4: 715-719. Review.

6. Zhang, J., Neisa, R., and Mao, Y. Oncogenic APC mutants impair the mitotic checkpoint through direct interaction with Mad2. Molecular Biology of the Cell 2009, 20: 2381-2388.

7. Zhang, J., Ahmad, S., and Mao, Y. BubR1 and APC/EB1 cooperate to maintain metaphase chromosome alignment. The Journal of Cell Biology 2007, 178: 773-784.

8. Mao, Y., Desai, A., and Cleveland, D.W. Microtubule capture by CENP-E silences mitotic checkpoint signaling. The Journal of Cell Biology 2005, 170: 873-880.

9. Mao, Y., Abrieu, A., and Cleveland, D.W. Activating and silencing the mitotic checkpoint through CENP-E dependent activation/inactivation of BubR1. Cell 2003, 114: 87-98.


Honors and Awards

2001 - 2002
Lopiccola Fellow, Pete Lopiccola Postdoctoral Fellowship Award in Cancer Research (UCSD Cancer Center)

2002 - 2004
NIH Postdoctoral Fellowship Award

2003
The James Kerr Award for Research Excellence, Ludwig Institute for Cancer Research (San Diego Branch)

2004 - 2007
The Leukemia & Lymphoma Society Special Fellow

2007 - 2008
Basil O'Connor Starter Scholar (March of Dimes Birth Defects Foundation)


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