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 ultimatively, us. In cancer, specific molecular interactions determine the formation of tumors and tumor-supporting tissue, including new blood vessels differentiated 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 and stem cell differentiation. 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.
HIGHLIGHTS OF OUR RESEARCH AT
MCG
2000: First organic synthesis of novel ceramide analogs that are water-soluble (natural ceramide is insoluble) and induce apoptosis (programmed cell death) specifically in cancer cells (JBC (2000) 275, 177-181).
2001/2: Discovery that in cancer as well as stem cells, expression of PAR-4 (prostate apoptosis response 4) is required to sensitize cells toward ceramide or novel ceramide analog-induced apoptosis (JBC (2001) 276, 44396-44404; and Cancer Letters (2002) 181, 55-64).
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 stem cell number during embryonic development (JCB (2003) 162, 469-479).
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 (JCB (2004) 167, 723-734). 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 (Glycoconjugate J. (2004) 21, 313-325; and JBC (2005) in press).
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 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.
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.
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