Joseph Nickels, Ph.D. MDL Pharmacogenomics Division Head
- 2006 – Editorial Board: Analytical Biochemistry.
- 1999-2006 Director, Graduate Program in Molecular and Cellular Biology and Genetics, Drexel University College of Medicine.
- 2005-2007 Associate Professor, Department of Biochemistry and Molecular Biology, Drexel University College of Medicine.
- 1999-2002 Basil O’Connor Scholar, March of Dimes Foundation.
- 1997-2005 Assistant Professor, Department of Biochemistry and Molecular Biology, DrexelUniversity College of Medicine.
- 1994-97 Postdoctoral Fellow, New Jersey Commission on Cancer Research.
- 1993-97 Post-doctoral fellow, Department of Molecular Biology, Princeton University, Advisor: Jim
- Broach, Ph.D. Studied ceramide signaling and the role of ceramide-activated protein phosphatase (CAPP) in regulating the yeast cell cycle.
- 1989-93 Ph.D. Microbiology and Molecular Genetics, UMDNJ/Rutgers University. Studied phosphoinositide signaling in the yeast S. cerevisiae. Advisor: George Carman, Ph.D.
- Adhoc manuscript reviewer Journal of Biological Chemistry, Genetics, Molecular and Cellular Biology, Microbiology, Eukaryotic Cell, Current Biology, Molecular Biology of the Cell, Biochmica and Biochim Biophys Acta.
- Adhoc grant reviewer Canadian Research Council, National Science Foundation, Swiss Research Foundation.
- Member of Genetics Society of America, American Association for the Advancement of Science, American Society for Microbiology, American Society for Biochemistry and Molecular Biology.
- Currently isolating novel antifungal targets through uncovering the molecular basis for induced sterol gene expression in response to blocks in sterol biosynthesis in several yeast species.
- Isolating novel protein phosphatase 2A (PP2A) targets through elucidating the role of PP2A and CAPP in cell cycle regulation and endocytosis. These targets may have future potential as drug targets for cancer and diabetes.
- Exploring the role of the putative lipid transporter, Arv1, in sterol trafficking, cardiovascular disease, and polarized growth in yeast and humans.
Research Interests:
Our laboratory has a basic research focus in two different areas. The first area is aimed at understanding the signals that are used in controlling the cell cycle. Under normal circumstances, the cell cycle is carefully controlled to ensure that cells replicate at the "right time." A loss of appropriate cell cycle signaling can result in uncontrolled growth, which often manifests itself as a form of cancer. The other focus of our laboratory is directed at an understanding of the checks and balances governing sterol synthesis. Sterol synthesis is one of the major therapeutic targets in the control of heart disease. Both of these research projects involve extremely complicated regulatory signals. To aid in our basic understanding, we have adopted the yeast system as a means of addressing our experimental questions.
Research Program
The Control of Cell Differentiation in Eukaryotes The sphingolipid ceramide has emerged as a novel second messenger that mediates the biological responses of cells to a number of key growth modulators. Strikingly, the majority of responses elicited by ceramide-mediated pathways are anti-proliferative and can result in apoptosis, cell-cycle arrest and/or terminal differentiation of cells. Thus, the cell factors that mediate the ceramide signaling cascade may represent novel therapeutic targets for the intervention of many types of cancer. However, answers concerning the downstream components and the connection they have within the mammalian ceramide pathway remain elusive. With its ease of genetic and biochemical manipulation, the yeast Saccharomyces cerevisiae offers a novel and complementary means to dissect the biology of ceramide signaling in eukaryotes. The degree of homology between the yeast and mammalian ceramide pathways is substantial. In yeast, as in mammalian cells, the ceramide pathway activates a heterotrimeric protein phosphatase 2A (PP2A) species that is involved in transducing a G1 cell cycle arrest1. Thus, PP2A activity plays a critical role in mediating ceramide signaling in eukaryotes. Our laboratory has recently discovered that yeast cells also require proper PP2A activity to initiate and progress normally through the terminal differentiation state of sporulation. When induced to sporulate, yeast diploids cells lacking PP2A activity initiate an invasive growth pattern rather than progress through meiosis. We are currently using genetic and biochemical approaches as a means to understand at the molecular level how PP2A activity regulates the sporulation process in yeast. We anticipate that some or all of the cell factors regulated by PP2A during sporulation will plays roles in ceramide signaling, as well.
Mechanisms Regulating Sterol Biosynthesis and Gene Expression Heart disease is responsible for over half of the deaths in the Western World. Current therapeutic strategies aimed at preventing this disease focus on drugs that block or attenuate sterol synthesis. There are multiple regulatory mechanisms designed to maintain sterol homeostasis in eukaryotic cells. Our goal is to elucidate novel transcriptional mechanisms involved in sensing cellular sterol levels in order to test new sites for regulation of sterol levels in eukaryotic cells. We have evidence in yeast for a novel transcriptional regulation of three genes, ERG25, ERG26, and ERG27, which encode for the enzymes that convert 4’, 4’- dimethylzymosterol to zymosterol2. Zymosterol is the immediate precursor of the major yeast sterol, ergosterol. Our data suggest that the transcription of these three genes is up-regulated by their substrates, the dimethylzymosterol to zymosterol intermediates. Therefore, the conversion of 4’, 4’-dimethylzymosterol to zymosterol may represent a rate-limiting step in sterol biosynthesis. Our hypothesis is that a novel regulatory mechanism exists that is designed to sense, as well as modulate zymosterol levels in cells. We are testing this hypothesis in Saccharomyces cerevisiae because it is a model system for the study of st3rol regulation that allows powerful genetic and biochemical analyses to be performed. To date, our work has focused on the transcriptional regulation of the ERG26 gene, as we have found that the loss of activity of its gene product causes the accumulation of zymosterol intermediates and the up-regulation of expression of ERG25, ERG26, and ERG27.
Representative Publications
- Villasmil ML, Bower M, Ansbach A, Nickels JT. The putative lipid transporter, Arv1, is required for mating in Saccharomyces cerevisiae. Yeast Genetics and Molecular Biology Meeting, Toronto, Canada. July 22-27, 2008.