Robert A. Mitchell, Ph.D.

Education:

B.S. in Immunology, University of Iowa School of Medicine, Iowa City, IA, 1989
Ph.D. in Experimental Pathology, Albany Medical College, Albany, New York, 1998
Postdoctoral Fellowship, Picower Institute for Medical Research, Manhasset, NY, 1998-01

Curriculum Vitae

Current Positions:

Associate Professor, Department of Medicine, University of Louisville
Associate Professor, Department of Biochemistry & Molecular Biology, University of Louisville – Joint Appointment
Associate Faculty Member, Department of Microbiology & Immunology, University of Louisville

Contact Information:

Robert A. Mitchell, Ph.D.
University of Louisville
Clinical and Translational Research Building
505 S. Hancock St.
Suite 404
Louisville, KY 40202
(502) 852-7698
(502) 852-3661

Email: robert.mitchell@louisville.edu

Research Description:

Dr. Mitchell’s laboratory work is primarily focused on characterizing the functional and mechanistic contributions of macrophage migration inhibitory factor (MIF) family member-dependent tumor progression. One active project involves the study of MIF and it’s only known family member, D-dopachrome tautomerase (D-DT) as they synergistically promote the growth and survival of human non-small cell lung carcinoma focusing on the AMPK and p53 tumor suppressor pathways (Brock et al. Negative regulation of AMPK activity by MIF family members in NSCLC. J. Biol. Chem. 287(45):37917-25; Brock et al. MIF Family Members Cooperatively Inhibit p53 Expression and Activity. PLoS One 16;9(6):e99795). Another very active area of investigation in the lab is the study of MIF and D-DT in a variety of tumor-stromal cell populations. For example, we recently identified an important role for monocyte/macrophage-derived MIF in promoting melanoma disease progression in mice (Yaddanapudi et al. Control of tumor-associated macrophage alternative activation by macrophage migration inhibitory factor. J Immunol. 190(6):2984-93.) and are currently evaluating the functional importance of MIF in circulating myeloid-derived suppressor cells (MDSCs) to human malignant melanoma disease progression. Our laboratory is utilizing whole body MIF-deficient, D-DT-deficient and various conditional MIF, D-DT and MIF:D-DT-double deficient mouse models to stringently evaluate the endogenous contributions of both MIF family members to both tumor-derived as well as stromal cell-derived tumor progression. Finally, a significant portion of our lab’s efforts are devoted to identifying novel - and optimizing existing - small molecule therapeutics specifically targeting MIF (Winner et al. A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells. Cancer Res. 68(18):7253-7.), D-DT or both. Given the importance of MIF family members to both tumor cell-dependent and stromal dependent pro-tumorigenic processes, the translational potential of these small molecule therapeutics is very high.

Literature Cited (15 Max.):

  1. J. Bernhagen, T. Calandra, R.A. Mitchell, S.B. Martin, K.J. Tracy, W. Voelter, K.R. Manogue, A. Cerami and R. Bucala (1993) MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature (365) 756-759. PMID: 8413654
  2. R.A. Mitchell, M. Bacher, J. Bernhagen, T. Pushkarskaya, M.F. Seldin and R. Bucala (1995) Cloning and characterization of the gene for mouse macrophage migration inhibitory factor (MIF). J. Immunol. (154)8 3863-3870. PMID: 7706726
  3. R.A. Mitchell, C. Metz, T. Peng and R. Bucala. (1999) Sustained MAP kinase and cPLA2 activation by macrophage inhibitory factor (MIF): Regulatory role in cell proliferation and glucocorticoid action. J. Biol. Chem. 274 18100-18106. PMID: 10364264
  4. R.A. Mitchell, H. Liao, J. Chesney, G. Fingerle-Rowson, J. Baugh, J. David and R. Bucala (2002) MIF sustains macrophage pro-inflammatory function by inhibiting p53: Regulatory role in the innate immune response. Proc. Natl. Acad. Sci. 99(1):345-350. PMID: 11756671
  5. J.D. Swant, B.E. Rendon, M. Symons and R.A. Mitchell (2005) Rho GTPase-dependent signaling is required for MIF-mediated expression of cyclin D1. J. Biol. Chem. 280(24):23066-23072. PMID: 15840582
  6. M. Winner, A.C. Koong, B.E. Rendon, W. Zundel and R.A. Mitchell (2007) Amplification of tumor hypoxic responses by MIF-dependent HIF stabilization. Cancer Res. 67(1):186-193. PMID: 17210698
  7. B.E. Rendon, I. Teneng, M. Zhao, M. Winner, Y. Al-Abed and R.A. Mitchell (2007) Regulation of human lung adenocarcinoma cell migration and invasion by MIF. J. Biol. Chem. 282:29910-18. PMID: 17709373
  8. A.M. Coleman, D. Xin, M. Zhao, M.W. Qian, R. Bucala, B.E. Rendonand R.A. Mitchell (2008) Cooperative Regulation of NSCLC Angiogenic Potential by MIF and its Homolog, D-Dopachrome Tautomerase. J. Immunol. 181(4):2330-7. PMID: 18684922
  9. M. Winner, J. Meier, S. Zierow,B.E. Rendon, G. Crichlow, R. Riggs, R. Bucala, L. Leng, N. Smith, E. Lolis, J.O. Trent and R.A. Mitchell (2008) A novel, MIF suicide substrate inhibits motility and growth of lung cancer cells. Cancer Res. 68(18):7253-7. PMID: 18794110
  10. D. Xin, B.E. Rendon, M. Zhao, M. Winner, A. Coleman and R.A. Mitchell (2010) The MIF homolog, D-dopachrome tautomerase (D-DT), promotes COX-2 expression through b-catenin-dependent and independent mechanisms. Mol. Cancer Res. 12:1601-1609. PMID: 21071513
  11. S.E. Brock, B.E. Rendon, K. Yaddanapudi and R.A. Mitchell (2012) Negative regulation of AMPK activity by MIF family members in NSCLC. J. Biol. Chem. 287(45):37917-25. PMID: 22988252
  12. K. Yaddanapudi, K. Putty, B.E. Rendon, A. Satoskar, A. Lasnik, J.W. Eaton and R.A. Mitchell (2013) Control of tumor-associated macrophage alternative activation by MIF. J Immunol. 190(6):2984-93. PMID: 23390297
  13. S.E. Brock, B.E. Rendon, D. Xin, K. Yaddanapudi and R.A. Mitchell (2014) Cooperative antagonism of p53 stabilization and activity by MIF family members in lung adenocarcinoma. PLOS One 16;9(6):e99795 PMID: 24932684
  14. K. Yaddanapudi and R.A. Mitchell (2014) Stromal-dependent tumor promotion by MIF family members. Cell. Signal. 26(12):2969-2978. PMID: 25277536
  15. K. Yaddanapudi, B.E. Rendon, G. Lamont, E.J. Kim, N. Al Rayyan, J. Richie, S. Albeituni, S. Waigel, A. Wise and R.A. Mitchell (2014) MIF is necessary for human melanoma MDSC induction and immune suppressive function. (Submitted)

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