John J. LaPres
Associate Professor
- B.S. 1988, University of Michigan, Ann Arbor, MI
- PhD 1997, Northwestern University, Evanston, IL
- 1997-2000, Postdoctoral Researcher, University of Wisconsin, Madison, WI
lapres@msu.edu
224 Biochemistry Building
Michigan State University
East Lansing, MI 48824-1319
Office: 517-432-9282
Lab: 517-432-9282
FAX: 517-353-9334
Gene Expression supplemental data (pdf)
Hep 3B supplemental data
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John J. LaPres Research Interests continued
Project #1: The role of HIF1 in metal-induced toxicity:
Cobalt and other divalent metals have been used as hypoxic mimics for many years. In fact, exposure to these metals leads to HIF1a stabilization and HIF1-dependent transcription. Metal exposure can also lead to cellular damage and premature cell death. We have begun exploring the hypothesis that this metal-induced damage is dependent upon HIF1 signaling. We have used genetically engineered cell lines to show that hypoxia signaling is important in metal-induced toxicity and genomic screens have revealed that the expression patterns between hypoxia and metals are very similar. This project is now focused on identifying specific genes that are important in this process using genomics and RNAi based models. In addition, we are attempting to elucidate the in vivo role of HIF1 signaling in metal-induced toxicity using engineered mice and exposure studies. Finally we are beginning to look at the metabolic consequences of metal exposure and attempting to link these changes to HIF1a genotype and specific metals. The ultimate goal of the project is to understand how metals influence HIF1 signaling and how this impacts the cell to promote a toxic response.
Project #2: Hypoxia, hydroxylation and tumorigenesis:
HIF1 signaling is primarily controlled at the level of protein stability. HIF1a, the cytoplasmic portion of the HIF1 dimer, is constantly transcribed and translated. Under normal oxygen tension, HIF1a is quickly hydroxylated by an iron- and oxygen-dependent enzyme called PHD. Once hydroxylated, the HIF1a protein is targeted for degradation by the Von Hippel Lindau (VHL) tumor suppressor protein. Under hypoxic conditions, the PHD is inhibited and HIF1a becomes stabilized and translocates to the nucleus, where it can dimerize with ARNT to form the functional transcription factor, HIF1. HIF1 regulates the expression of wide battery of adaptive genes that will allow the cell to cope with the hypoxic environment. These genes include vascular endothelial growth factor (VEGF), glycolytic enzymes and erythropoietin. This signaling cascade is critical for tumor growth and understanding the early events in cellular transformation is the goal of this project. It is focused on the relationship between PHD activity, HIF1 signaling and cellular transformation. Using engineered cell lines and various transformation assays, this project is attempting to determine if changes in PHD/HIF1/hypoxia signaling can alter a cell's tumor forming potential. In addition, this project is using metabolite profiling to characterize the biochemical consequences of these changes and their relationship to a transformed phenotype.
Project #3 The role of secondary proteins in aryl hydrocarbon receptor biology:
The aryl hydrocarbon receptor (AHR) is responsible for sensing environmental contaminants, such as 2,3,7,8-tetrachloro-r-dioxin (TCDD) and instigating the cellular response to their presence. Primarily, this response involves the activation of cytochrome p450 enzymes. The AHR is also responsible for regulating the toxic effects of these ligands upon biological systems. For example, TCDD is recognized as one of the most harmful chemicals known to man but it is mostly non-toxic in mice that have no functional AHR. However, the expression pattern of the AHR does not completely explain the pleiotropic effects seen in different tissues following exposure to AHR agonist, like TCDD. We have hypothesized this pleiotropy is dependent upon varying degrees of secondary proteins that can influence AHR biology through direct interaction with the AHR or through modulation of the activity of proteins already known to bind the receptor, such as Hsp90 and ARA9. To address this hypothesis we have begun a series of screens looking for proteins capable of interacting with the AHR. This project focuses on characterizing the effects of these identified proteins on AHR signaling and AHR-mediated toxicity. This project uses state of the art proteomic technology hear at Michigan State University and several engineered cell lines and animal models. The ultimate goal is to link tissue specific AHR binding partners with tissue specific toxicity with the hopes of understanding the signaling necessary to instigate the pathology of TCDD, as well as other AHR agonist, exposure.