P. Todd Stukenberg
Professor of Biochemistry & Molecular Genetics
Ph.D., Cornell University Medical College
Mechanisms of Mitotic Regulation

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Defects in chromosome segregation can generate aneuploidy, a condition that is found in almost all human tumors and is a major cause of miscarriages and birth defects. The complex process of chromosome segregation must be highly coordinated to ensure fidelity and prevent aneuploidy. Kinetochores are central players in mitosis. Kinetochores are complex protein machines that assemble on each chromatid. They link chromosomes to microtubules and are the motors that move chromosomes on the mitotic spindle. Kinetochores also ensure that all chromatids are attached before they are segregated. If kinetochores are not attached to microtubules, they generate signals that prevent the cell cycle machinery from entering anaphase, a process referred to as the spindle checkpoint.

In the Stukenberg lab we study how kinetochores work and how they are regulated. Surprisingly we found that a single complex, known as the Ndc80 complex, is central to both the motor and signaling roles of the kinetochore. We are intensively studying this fascinating group of four proteins. These studies are determining how the kinetochore uses the energy stored within a microtubule to perform the work of moving chromosomes. In addition we are determining how kinetochores initiate the spindle checkpoint signal and turn it off after microtubules attach.

We also study the Aurora B kinase. Aurora B regulates kinetochores and plays an important role in the spindle checkpoint. We are dissecting how Aurora B itself is regulated and identifying the important substrates that are regulated by Aurora B. Our studies are uncovering how Aurora B can coordinate numerous mitotic processes and we have found that it has an exciting role to provide spatial information for mitotic events. Since Aurora kinase inhibitors are currently undergoing clinical trials as chemotherapeutics, these studies are directing clinicians to more effectively utilize this new class of drugs.

Selected References

Matson DR, Demirel PB, Stukenberg PT, Burke DJ. (2012) "A conserved role for COMA/CENP-H/I/N kinetochore proteins in the spindle checkpoint." Genes Dev. Mar 26:542-7. doi: 10.1101/gad.184184.111. [PubMed]

Zyłkiewicz E, Kijańska M, Choi WC, Derewenda U, Derewenda ZS, Stukenberg PT. (2011) "The N-terminal coiled-coil of Ndel1 is a regulated scaffold that recruits LIS1 to dynein." J Cell Biol. Feb 192:433-45. doi: 10.1083/jcb.201011142. Epub 2011 Jan 31. [PubMed]

Knowlton AL, Vorozhko VV, Lan W, Gorbsky GJ, Stukenberg PT. (2009) "ICIS and Aurora B coregulate the microtubule depolymerase Kif2a." Curr Biol. May 19:758-63. doi: 10.1016/j.cub.2009.03.018. Epub 2009Mar 26. [PubMed]

Miller SA, Johnson ML, Stukenberg PT. (2008) "Kinetochore attachments require an interaction between unstructured tails on microtubules and Ndc80(Hec1)." Curr Biol. Nov 18(22):1785-91. doi: 10.1016/j.cub.2008.11.007. [PubMed]

Fuller BG, Lampson MA, Foley EA, Rosasco-Nitcher S, Le KV, Tobelmann P, BrautiganDL, Stukenberg PT, Kapoor TM. (2008) "Midzone activation of aurora B in anaphase produces an intracellular phosphorylation gradient." Nature. Jun 453(7198):1132-6. doi: 10.1038/nature06923. Epub 2008 May 7. [PubMed]

Rosasco-Nitcher SE, Lan W, Khorasanizadeh S, Stukenberg PT. (2008) "Centromeric Aurora-B activation requires TD-60, microtubules, and substrate priming phosphorylation." Science. Jan 319(5862):469-72. doi: 10.1126/science.1148980. [PubMed]

Emanuele MJ, Stukenberg PT. (2007) "Xenopus Cep57 is a novel kinetochore component involved in microtubule attachment." Cell. Sep 130:893-905. [PubMed]