Associate Professor, Institute of Molecular Medicine &
Genetics, Department of Medicine
Ph.D., University of Cologne, Cologne, Germany, 1990
Lab website: http://www.georgiahealth.edu/institutes/immag/Bieberich/homepage.htm
Dr. Erhard Bieberich
Institute of Molecular Medicine and Genetics
Medical College of Georgia
1120 15th Street Room CA-4012
Augusta, GA 30912
The greatest challenge in molecular cell biology is to understand the translation of a molecular interaction into a biological phenotype . During embryonic development, this molecular interaction regulates stem cell migration and germ layer formation, two processes essential for shaping the human embryo and ultimately, us. In cancer, specific molecular interactions determine the formation of tumors and tumor-supporting tissue from stem cells. In our group, we study how the molecular interaction of a particular lipid (ceramide) with a cell signaling protein (protein kinase C (PKC)) regulates embryonic development, stem cell differentiation, and cancer. We apply multidisciplinary approaches ranging from molecular modeling and organic chemistry to molecular and developmental biology. Our work has shown that there is a close relationship between tumor and stem cell biology. Eventually, this knowledge will help us to better understand the coordinated development of the embryo, to improve stem cell therapy, and to fight cancer.
2000: Organic synthesis and characterization of novel ceramide analogs. We have, for the first time, synthesized novel ceramide analogs that are water-soluble (natural ceramide is insoluble) and induce apoptosis (programmed cell death) specifically in cancer cells.
2001/2: Discovery that in cancer as well as stem cells, expression of the atypical PKC (aPKC) inhibitor protein PAR-4 (prostate apoptosis response 4) is required to sensitize cells toward ceramide or novel ceramide analog-induced apoptosis.
2003: First description of the asymmetric distribution of PAR-4 during stem cell division. Only the PAR-4 expressing daughter cell dies by ceramide-induced apoptosis. We have proposed that this mechanism regulates the stem cell number during embryonic development.
2004: Discovery that PAR-4 and Oct-4 (pluripotency marker for stem cells) are co-expressed in tumorigenic stem cells. Incubation of stem cells with novel ceramide analogs eliminates tumor-(teratoma) forming cells and promotes neural differentiation of stem cell transplants. This treatment will significantly improve stem cell therapy.
2004/5: Novel model for the regulation of PKC-dependent cell signaling pathways by ceramide : SLIPS (sphingolipid-induced protein scaffolds). Ceramide can be good (PKC activator) or bad (PKC inhibitor) for the cell, depending on the protein complex induced by ceramide binding.
2006: Activation of atypical PKC (aPKC) by binding to ceramide. Ceramide activates aPKC and promotes NF-κB-dependent cell survival unless PAR-4 is expressed. PAR-4 binds to and inhibits ceramide-associated aPKC, downregulates NF-κB, and induces cell death. This is the first study visualizing the interaction of ceramide with a protein complex (aPKC/PAR-4). 2007: Ceramide is critical for cell polarity. The SLIPS concept predicts that ceramide-mediated activation will also trigger factors downstream of aPKC. One of the most important processes downstream of aPKC is cell polarity. A recent study from our laboratory, for the first time, demonstrates that primitive ectoderm cells fail to establish epithelial morphology and apicobasal polarity in the absence of ceramide. Polarity and primitive ectoderm formation is restored by novel ceramide analogs. Also, first polyclonal antibody against ceramide produced in our laboratory. 2008: Ceramide is critical for neural precursor cell migration and brain development. Since aPKC is also essential for neural precursor cell migration, we tested if ceramide regulates aPKC in this process. Using a combination of in vitro and in vivo approaches, the most recent study clearly shows that ceramide activates neural precursor cell migration. Without ceramide, cortical development is severely disturbed and shows a phenotype similar to aPKC deficiency.
2009: Ceramide is fundamental for cell polarity and ciliogenesis. In addition to its critical role for cell migration, we found that ceramide is enriched in a pericentrosomal compartment at the base of primary cilia. Depleting cells of ceramide abolished ciliogenesis, while supplementation of ceramide-deficient cells with exogenous ceramide or ceramide analogs restored cilia formation. These results show that a ceramide-enriched compartment critically regulates cell polarity-related processes such as ciliogenesis. 2010: Good ceramide gone bad and the “Lucifer effect”: Our model proposed in 2004 suggesting that ceramide can be good or bad depending on the cellular context is now further substantiated in three of our projects: fetal alcohol syndrome, Alzheimer’s disease, and breast cancer. In these biological processes, ceramide that is useful for cell polarity and migration has gone bad and induces cell death due to the expression of the ceramide sensitizer protein PAR-4 (Lucifer effect).
Our studies clearly show how a particular molecular interaction (lipid-protein binding) translates into similar, but unrelated disease phenotypes. We are now testing if these phenotypes can be corrected by detoxifying ceramide, or if ceramide can be toxified to kill cancer cells. Selected Publications (up to 10)
Wang, G. Krishnamurthy, K., and Bieberich, E. (2009) Regulation of primary cilia formation by ceramide. J. Lipid Res. , in press.
Wang, G., Krishnamurthy, K., Umapathy, N.S., Verin, A.D., and Bieberich E. (2009) The carboxyl-terminal domain of atypical protein kinase Czeta binds to ceramide and regulates junction formation in epithelial cells. J Biol Chem. 21, 14469-14475.
Krishnamurthy, K., Wang, G., Rokhfeld, D., and Bieberich, E. (2008) Deoxycholate promotes survival of breast cancer cells by reducing the level of pro-apoptotic ceramide. Breast Cancer Res. 10, R106.
Wang, G., Krishnamurthy, K., Chiang, Y.-W., Dasgupta, S., and Bieberich, E (2008) Regulation of neural progenitor cell motility by ceramide and potential implications for mouse brain development, J. Neurochem. 106, 718-733.
Wang, G., Silva, J., Dasgupta, S., and Bieberich, E. (2008) Long-chain ceramide is elevated in Presenilin 1 (PS1M146V) mouse brain and induces apoptosis in PS1 astrocytes. Glia 56, 449-456.
Krishnamurthy, K., Wang, G., Silva, J., Condie, B.G., and Bieberich, E. (2007) Ceramide regulates atypical PKCzeta/lambda-mediated cell polarity in primitive ectoderm cells: A novel function of sphingolipids in morphogenesis. J Biol Chem. 282, 3379-3390.
Bieberich, E., Silva, J., Wang, G., Krishnamurthy, K. and Condie, B.G. (2004) Selective apoptosis of pluripotent mouse and human stem cells by novel ceramide analogs prevents teratoma formation and enriches for neural precursors in ES-cell derived neural transplants. J. Cell Biol. 167, 723-734.
Bieberich, E. (2004) Integration of glycosphingolipid metabolism and cell-fate decisions in cancer and stem cells: Review and Hypothesis. Glycoconj. J. 21, 313-325.
Bieberich, E., MacKinnon, S., Silva, J., Noggle, S., and Condie, B. (2003) Regulation of cell death in mitotic neural progenitors by asymmetric distribution of prostate apoptosis response-4 (PAR-4) and simultaneous elevation of endogenous ceramide. J. Cell Biol., 162, 469-479.