F. Michael Hoffmann, Ph.D.

Romnes Professor of Oncology and Medical Genetics

B.S., 1973, Chemistry, Rensselaer Polytechnic Institute, NY
Ph.D., 1979, Biochemistry, Cornell University, NY
Postdoctoral research: Massachusetts Institute of Technology and Harvard University

Office: 320 McArdle Laboratory
Telephone: Office - (608) 263-2890; Lab - (608) 262-8854
Email: hoffmann@oncology.wisc.edu

Lab Home Page

Small Molecule Screening & Synthesis Facility

Research Interests: How does the Smad-dependent TGF-β signaling pathway mediate such different cellular responses in different cell types and specifically in pancreatic cancer, diabetic nephropathy and muscular dystrophy.

Research Description: The TGF-β signal transduction pathway plays key roles in normal functions such as wound healing and suppression of the immune system.  But TGF-β signaling has also been implicated as a factor in cancer, as a causative agent in all fibrotic diseases including diabetic nephropathy, and as an exacerbating factor in muscle weakness in muscular dystrophy.  In human tumors, such as pancreatic tumors, the normal growth inhibitory function of TGF-β is lost.  In some advanced tumors, the pathway is altered such that TGF-β stimulates proliferation of the cancer cell.  TGF-β also promotes tumor growth and spread by enhancing cell migration, angiogenesis, immune suppression, and stromal activation.

The Smad proteins and several Smad-interacting transcription factors provide an array of new targets that could be potential sites for therapeutic intervention. There are currently no therapeutic agents that act on these targets in the TGF-β pathway.

Our working hypothesis is that inhibition of specific Smad protein-protein interactions will selectively attenuate certain cellular responses to TGF-β, e.g., inhibit fibrosis but maintain cell proliferation control and immunosuppression by TGF-β.

We are using a genetic approach to define protein binding hotspots on the surfaces of Smad proteins and characterizing the effects of these missense mutations on Smad functions in Smad-deficient cells. 

My interests in academic drug discovery and roles as the faculty advisor to the campus high throughput screening facility and co-leader of the Experimental Therapeutics Program in the Carbone Cancer Center have led to numerous collaborative projects with other UW-Madison faculty.

Selected recent publications

Schiro, M. M., Stauber, S. E., Peterson, T. L., Krueger, C., Darnell, S. J., Satyshur, K. A., Drinkwater, N. R., Newton, M. A., and Hoffmann, F. M.  Mutations in Protein-Binding Hot-Spots on the Hub Protein Smad3 Differentially Affect Its Protein Interactions and Smad3-Regulated Gene Expression.  PLoS One, 6(9):e25021, 2011.

Krueger, C., and Hoffmann, F. M.  Identification of Retinoic Acid in a High Content Screen for Agents that Overcome the Anti-myogenic Effect of TGF-Beta-1.  PLoS One, 5(11):e15511, 2010.

Luo, Y., Li, W., Ju, J., Yuan, Q., Peters, N. R., Hoffmann, F. M., Huang, S.-X., Bugni, T. S., Rajski, S., Osada, H., and Shen, B.  Functional Characterization of TtnD and TtnF, Unveiling New Insights into Tautomycetin Biosynthesis.  J. Am. Chem. Soc., 132: 6663-6671, 2010.

Mehraein-Ghomi, F., Basu, H. S., Church, D. R., Hoffmann, F. M., and Wilding, G.  Androgen Receptor Requires JunD as a Coactivator to Switch on an Oxidative Stress Generation Pathway in Prostate Cancer Cells.  Cancer Res., 70: 4560-4568, 2010.

Powell, E., Huang, S.-X., Xu, Y., Rajski, S. R., Wang, Y., Peters, N., Guo, S., Xu, H. E., Hoffmann, F. M., Shen, B., and Xu, W.  Identification and Characterization of a Novel Estrogenic Ligand Actinopolymorphol A.  Biochem. Pharmacol., 80: 1221-1229, 2010.

Das, S., Becker, B. N., Hoffmann, F. M., and Mertz, J. E.  Complete Reversal of Epithelial to Mesenchymal Transition Requires Inhibition of Both ZEB Expression and the Rho Pathway.  BMC Cell Biol., 10:94, 2009. 

Ewald, J. A., Peters, N., Desotelle, J. A., Hoffmann, F. M., and Jarrard, D. F.  A High-Throughput Method to Identify Novel Senescence-Inducing Compounds.  J. Biomol. Screen., 14: 853-858, 2009.

Ju, J., Li, W., Yuan, Q., Peters, N. R., Hoffmann, F. M., Rajski, S. R., Osada, H., and Shen, B.  Functional Characterization of ttmM Unveils New Tautomycin Analogs and Insight into Tautomycin Biosynthesis and Activity.  Org. Lett., 11:  1639-1642, 2009.

Ju, J., Rajski, S. R., Lim, S.-K., Seo, J.-W., Peters, N. R., Hoffmann, F. M., and Shen, B.  Lactimidomycin, Iso-migrastatin and Related Glutarimide-Containing 12-Membered Macrolides Are Extremely Potent Inhibitors of Cell Migration.  J. Am. Chem. Soc., 131:  1370-1371, 2009.

Hoffmann, F. M., Cui, Q., Lim, S. K., and Zhao, B. M.  Targeting Smad-dependent TGF-β Signaling with Peptide Aptamers.  In:  S. B. Jakowlew (Ed.), Transforming Growth Factor-β in Cancer Therapy, Volume II, Chapter 45.  Totowa, NJ:  Humana Press, 2008.

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