Research Team Leader
Division of Pharmacogenomics
Medical Diagnostics Laboratories
2439 Kuser Road
Hamilton, NJ 08691
609-570-1046
Fax: 609-570-103
Joseph.Nickels@DrexelMed.edu

 
Dr. Nickels has cut back to part-time teaching in order to focus on the exciting research underway at Medical Diagnostics Laboratories.

Education:
Ph.D. (1993) Microbiology & Immunogenetics
Unversity of Medicine and Dentistry, New Jersey (UMDNJ)

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.

Selected Publications

1. Nickels, J.T., and Broach, J.R. (1996). A ceramide-activated protein phosphatase mediates ceramde-induced G1 arrest of Saccharomyces cerevisiae. Genes & Dev. 10: 382-394.

2. Henry, K.W., Nickels, J.T., and Edlind, T.D. (2000). Upregulation of ERG genes in Candida species by azoles and other sterol biosynthesis inhibitors. Antimicrob. Agents & Chemother. 44: 2693-2700.