Developmental Biology Program

Address

W406
Fox Chase Cancer Center,
333 Cottman Ave.
Philadelphia, PA 19111

Office tel.: 215-728-2860
Lab tel.: 215-728-3885
Fax: 215-728-3616
E-mail: ea_golemis@fccc.edu

Education

Bryn Mawr College, B.A. (Biology and English)1983

Massachusetts Institute of Technology, Ph.D. Biology (focus: murine retroviruses and leukemogenesis), 1988

Massachusetts General Hospital Department of Molecular Biology and Harvard Medical School Department of Genetics, post-doctoral studies (yeast biotechnology/development of a two-hybrid system) 1993

Research Interests

• Connections between cell shape and cell division controls, and linked deregulation of these processes in cancer. Complex protein interactions in cell signaling.

Key words: HEF1, HEI-C, HEI10, two-hybrid, protein interactions

Search PubMed for articles

Description of Research

Our laboratory is interested in the dialog between cell shape controls and the cell cycle machinery in cancer. As theoretical background to this work, we consider that organismal development requires the synchronized interaction of cell differentiation, polarization, and division controls to enable the creation of highly organized structures from an isolated oocyte. At present, although the mechanisms by which these different processes are coordinated are not well understood, studies predominantly in lower eukaryotes have led to the identification of a number of proteins that act at cell-cell or cell-substrate interfaces in interphase, and at the mitotic machinery in M-phase. The complex functions of these proteins allow the direct specification of cleavage plane to be coordinated with the establishment or maintenance of a polarized cellular. A number of the proteins identified in these studies have homologs with presumably orthologous functions in higher eukaryotes. However, studies of mammalian signaling proteins typically have not focused on very early development, but rather emphasize the study of cell processes and protein function in 2-dimensional cell culture models, where the coordination of cell division polarity with cellular attachment status is less readily perceived and analyzed. Given that progression from differentiated cells, organized in 3 dimensions in tissues to an undifferentiated dysplastic cellular mass is absolutely characteristic of solid tumors, it is likely that proteins that control these changes will have important functions in cancer. We have focused our work on characterizing 3 proteins discovered by our laboratory that possess dual functions at points of cell-cell interaction and in control of the cell division cycle. Based on our studies, the HEF1, HEI-C, and HEI10 proteins have been characterized as links between the cell attachment and the mitotic machinery.

Recent Publications

Pugacheva, E.N.,and Golemis, E.A. HEF1 regulates centrosomal maturation and spindle formation through control of the Aurora A kinase. Nature Cell Biol. 7:937-946, 2005.

Dadke, D., Jarnik, M., Pugacheva, E.N., Singh, M.K., and Golemis, E.A. Deregulation of HEF1 impairs M-phase progression by disrupting the RhoA activation cycle. Mol Biol Cell 17:1204-1217, 2006.

Pugacheva, E.N., Roegiers, F., and Golemis, E.A. Interdependence of cell attachment and cell cycle signaling. Curr. Opin. Cell Biol. 18:507-515, 2006

Singh, M.K., Nicolas, E., Gherraby, W., Dadke, D., Lessin, S., and Golemis, E.A. HEI10 negatively regulates cell migration by inhibiting cyclin B/Cdk1 and other pro-motility proteins. Oncogene, Epub Feb12, 2007.

Pugacheva, E.N., Jablonski, S.A., Hartman, T.R., Henske, E.P, and Golemis, E.A. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 129:1351-1363, 2007.

Lab

Rotation Projects

General Introduction. The major source of cancer morbidity and mortality is uncontrolled metastasis. Our laboratory seeks insight into the molecular basis for metastasis, addressing the hypothesis that the fundamental cell processes regulating cell shape, attachment, migration, and division are interconnected through the use of central coordinating proteins that are points of cellular vulnerability. For example, elevated expression of the protein HEF1/NEDD9/Cas-L, a major focus of study in the laboratory, is an important determinant of metastasis in melanoma, breast cancer, and glioblastoma, and acts cooperatively with the important oncoprotein Ras. Our work on HEF1 addresses the complex biology of this protein in mitotic regulation, function of cilia, and in signal transduction. This work is complemented by studies of functionally related proteins, by analysis of the role of the tumor microenvironment in influencing cell transformation, and by exploration of novel therapeutic agents targeting HEF1-Ras signaling.

Projects.

1. We are using HEF1 knockout mice to explore the idea that loss of HEF1 conditions the incidence of metastasis in breast cancer tumor models. We are specifically exploring the interaction of HEF1 mutation with proteins in the Ras signaling pathway, and with the Aurora kinase mitotic machinery.
2. We have determined that HEF1-Aurora A signaling regulates the disassembly of cilia. Defects in cilia are associated with a large number of clinically important diseases, including polycystic kidney disease (PKD), Bardet-Biedl Syndrome, Kartagener Syndrome, and others. We are using cell culture and in vivo experiments to explore the functional interactions between HEF1 and Aurora A, and proteins in the PKD signaling pathway.
3. With clinician collaborators, we are using protein interaction-based informatic approaches in conjunction with targeted siRNA library, mid-throughput screening, to identify Ras pathway-related genes that condition HEF1-induced cell migration, and modify response to clinical agents.
4. Together with our collaborator Fabrice Roegiers, we have developed a novel Drosophila model to study the function of the HEF1 protein family. Ongoing work analyzes the developmental defects and genetic interactions of Drosophila HEF1.

Lab personnel:

Ilya G. Serebriiskii, Ph.D., Staff Scientist
Mahendra K. Singh, Ph.D., Postdoctoral Fellow
Nadezhda Tikhmyanova, M.S., Graduate Student, Drexel School of Medicine
Eugene Izumchenko, M.S., Graduate Student, Ben-Gurion University of the Negev
Olga Plotnikova, M.S., Russian State Medical University