Calkins, Marcus - Date Last Updated: 10/21/2008

Marcus Calkins Phd Fall 2008
Started 2002
Native of Oregon
Lab of Jeffrey Johnson, PhD

Undergraduate Work
Oregon State University
Bachelor of Science, Chemical Engineering (1999)

Research as of August 2006
The antioxidant response element is an enhancer that has been shown to be important in the coordinate transcription of a set of genes that are essential to combating the effects of oxidative stress. The main transcription factor associated with the induction of this antioxidant response is a cap ‘n collar protein called NF-E2-related factor-2 (Nrf2). Under normal conditions, Nrf2 is sequestered in the cytosol by association with a protein known as Keap1. Upon induction by cell signaling mechanisms or xenobiotic or oxidative stress, Nrf2 is released and translocates to the nucleus where it dimerizes with small Maf proteins and drives the transcriptional response. This response has been shown to combat many xenobiotics and oxidative insults both in cell culture and in animals.

In neurons, mitochondrial complex II inhibiting chemicals cause cell death by an oxidative stress dependant mechanism. In animals, malonate and 3-nitropropionic acid target a specific highly-vulnerable neuronal subpopulation within the striatum and lead to a syndrome that is reminiscent of the genetic disease Huntington’s disease (HD). We have shown that Nrf2 plays an integral role in preventing mitochondrial complex II induced neuronal death and striatal degeneration both in neuronal culture and in whole animals. In order to extend this finding, we are investigating the role of Nrf2 in genetic-murine models of HD. Furthermore we are investigating the ability of small molecule activators of the Nrf2 pathway to prevent degeneration in genetic models of HD and chemical models of striatal degeneration.

Funding
National Research Service Award Predoctoral Traineeship (NIEHS Training Grant T32, 01/04 - 12/06)

Publications
Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, Kraft AD, Lee JM, Li J, Johnson JA. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal. 2008 Aug 21. [Epub ahead of print]

Li J, Calkins MJ, Johnson DA, Johnson JA – Nrf2 dependent ARE-driven antioxidant pathway in neuroprotection. Neuroprotection (Methods in Molecular Biology) in press

Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA - Nrf2, a multi-organ protector? FASEB J. 2005 Jul;19(9):1061-6. PMID: 15985529 [PubMed - indexed for MEDLINE]

Calkins MJ, Jakel RJ, Johnson DA, Chan K, Kan YW, Johnson JA - Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc Natl Acad Sci USA.2005 Jan 4;102(1);244-9. Epub 2004 Dec 20. PMID: 15611470 [PubMed - indexed for MEDLINE]

Li J, Johnson D, Calkins M, Wright L, Svendsen C, Johnson J - Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. Toxicol Sci. 2005 Feb;83(2):313-28. Epub 2004 Nov 3. PMID: 15525690 [PubMed - indexed for MEDLINE]

Lee JM, Calkins MJ, Chan K, Kan YW, Johnson JA. - Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem. 2003 Apr 4;278(14):12029-38. Epub 2003 Jan 28. PMID: 12556532 [PubMed - indexed for MEDLINE]

Posters
Investigations into the Therapeutic Potential of Transcription Factor NF-E2 Related Factor 2 (Nrf2) in a Mouse Model of Huntington’s Disease. M.J. Calkins1,2, Jeffrey A. Johnson1,2,3. 1Molecular and Environmental Toxicology, University of Wisconsin, Madison, WI, 2School of Pharmacy, University of Wisconsin, Madison, WI, 3Waisman Center, University of Wisconsin (Poster presented at 2006 CAGn meeting in Boston by Marcus Calkins)

Antioxidant Response Element Signaling in Neural Progenitor Cells and Grafts; Potential Protection Against Neurotoxicants. M. Calkins 1,2 , J. Li4, D.A. Johnson2, and J.A. Johnson1,2,3. 1Molecular and Environmental Toxicology, University of Wisconsin, Madison, WI, 2School of Pharmacy, University of Wisconsin, Madison, WI, 3Waisman Center, University of Wisconsin, and 4Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children’s Research Hospital, Memphis, TN (Poster presented at 2006-SOT in San Diego by Marcus Calkins)

Sensitivity to mitochondrial complex II inhibitors, malonate and 3-nitropropionic acid in Nrf2 knockout mice. M.J. Calkins 1,2 , R.J. Jakel1,3, and J.A. Johnson1,2,3. 1Molecular and Environmental Toxicology, University of Wisconsin, Madison, WI, 2School of Pharmacy, University of Wisconsin, Madison, WI, 3Waisman Center, University of Wisconsin, (Poster presented at 2005-SOT in New Orleans by Marcus Calkins)

Date Last Updated: 10/21/2008 webteam@med.wisc.edu