Previous and current research:
The physical separation of daughter cells during cytokinesis represents the final step of cell division and provides the basis for cell multiplication during proliferation and development. Cytokinesis also plays a key role in preventing aneuploidy, a hallmark of cancer cells.

A growing body of evidence links cytokinesis defects to genomic instability and tumorigenesis. Pharmacological or genetic inhibition of cytokinesis in murine cells leads to progressive aneuploidy and tumorigenesis. Furthermore, lesions in the tumor suppressor genes BRCA2 and LATS1 perturb the successful completion of cytokinesis.

In animal cells, cytokinesis is accomplished by the constriction of an actomyosin-based structure, called the contractile ring. This constriction drives ingression of the cleavage furrow between the two sets of segregated sister genomes at anaphase.The conserved RhoGEF protein Ect2 plays a pivotal role in initiating cytokinesis in animal cells. Recruitment of Ect2 to the central spindle at anaphase promotes local activation of the small GTPase RhoA, which induces assembly and ingression of the contractile ring at the equatorial cortex. Subsequent membrane fusion finally generates two physically distinct daughter cells.

Using a small-molecule inhibitor, we have discovered a key role for the mitotic kinase Polo-like kinase 1 (Plk1) in triggering the initiation of cytokinesis in human cells. Acute inhibition of Plk1 at anaphase abolishes RhoA accumulation at the equator, contractile ring formation, and cleavage furrow ingression. As a consequence, cells lacking Plk1 activity fail to divide and exit mitosis as tetraploid and bi-nucleated cells. We found that Plk1 regulates RhoA by promoting the interaction of the RhoGEF Ect2 with its central spindle anchor HsCyk-4. Currently, we are investigating the molecular basis for how Plk1 induces formation of the Ect2/Hs-Cyk4 complex, which lies at the heart of cleavage furrow induction in animal cells.

(A) Localization of Plk1 to the central spindle and (B) accumulation of RhoA at the cleavage furrow during anaphase in human cells. (C) Model depicting Plk1 function in triggering the initiation of cytokinesis. (D) Tetraploid and bi-nucleated interphase cells as a result of acute Plk1 inhibition and cytokinesis failure during the preceding cell division.

Future projects:

Molecular mechanisms regulating and executing cytokinesis in mammalian cells
We plan to use a combination of mass spectrometry and functional genomics to identify key molecules involved in different aspects of cytokinesis. Subsequently, we will employ cell biology, biochemistry, and time-lapse microscopy to unearth the molecular function of these factors. This will allow us to better understand how cells orchestrate microtubule, actin, and membrane action to bring about cell division at the right time and at the right place.

The causes and consequences of tetraploidy
The majority of human cancer cells are aneuploid and contain supernumerary spindle poles. A transient tetraploid intermediate, which has arisen through cell division failure or cell fusion, could provide the basis for both abnormalities on the road to cancer. We plan to investigate the effects of tetraploidy on genomic stability, mitotic dynamics, and tumorigenesis in mammalian cells. Furthermore, we are interested in determining the nature of the molecular lesions that are capable of inducing tetraploidy and all the adverse consequences thereof. Ultimately, we will use our findings in cultured cells to expand our studies to animal models. Characterizing the origin and fate of tetraploid cells will help us to understand the impact of cell division failure on tumorigenesis and might be useful to locate the Achilles heels of aneuploid cancer cells.