Biochemistry

Miles Pufall, PhD

Portrait

Assistant Professor of Biochemistry

Contact Information

Primary Office: 4-430 BSB
Iowa City, IA 52242
Primary Office Phone: 319-384-1820

Email: miles-pufall@uiowa.edu
Web: Pufall Laboratory

Education

BA, Chemistry, Oberlin College
MS, Toxicology, American University
PhD, Oncological Sciences, University of Utah

Post Doctoral, Cellular & Molecular Pharmacology, University of California, San Francisco

Education/Training Program Affiliations

Biosciences Graduate Program
Department of Biochemistry PhD
Interdisciplinary Graduate Program in Molecular and Cellular Biology
Medical Scientist Training Program

Research Summary

Proteins do not typically emerge from ribosomes ready to function. In fact, most proteins require precise signals to direct where, when, and how well to perform multiple functions. In my lab we study the structural and biophysical basis for how the glucocorticoid receptor (GR) responds to cellular signals. GR is a steroid activated transcription factor that is expressed in every tissue of the body. In each of these tissues GR performs a distinct function by binding different regions of the genome to affect regulation of gene programs. We are interested in understanding how signals change the conformation of GR to direct binding to specific genomic sites and expression of key genes. We have learned that once bound, the DNA sequence has a profound impact on GR structure and function, and we are pursuing how this influences recruitment of the correct complement of transcription factors to faithfully regulate genes. We study GR in particular because its central role in the treatment of childhood acute lymphoblastic leukemia (ALL). ALL is the most common childhood cancer and is highly treatable, with 90% of patients cured by standard chemotherapy. For the remaining 10%, the prognosis is grim. Surprisingly, treatment response is best predicted by whether ALL cells die when treated ex vivo with a single component of chemotherapy – glucocorticoids, suggesting a central role for GR in ALL treatment efficacy. Since both sensitive and resistant patients have normal levels of wild type GR, it is our hypothesis that important signaling pathways have been disrupted in resistant patients that affect the ability of GR to efficiently kill ALL cells. The long-term goals of my lab are to develop a deep understanding of how GR is fine-tuned by signals so that we can rationally develop compounds that will potently and specifically drive the genes that kill leukemias. Our immediate goals are to identify: all signals that have an impact on glucocorticoid induced cell death; GR regulated genes that induce cell death; and GR binding sites associated with these genes. In addition, we are elucidating how both drugs and DNA sequence change the structure of GR at these crucial genes.

Center, Program and Institute Affiliations

Holden Comprehensive Cancer Center

Selected Publications

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Watson L, Kuchenbecker K, Schiller B, Gross J, Pufall M, Yamamoto K.  The glucocorticoid receptor dimer interface allosterically transmits sequence-specific DNA signals.  Nature Structural & Molecular Biology.  2013 July. 20(7):876-83.
[PubMed]

Serafimova I, Pufall M, Krishnan S, Duda K, Cohen M, Maglathlin R, McFarland J, Miller R, Frödin M, Taunton J.  Reversible covalent targeting of noncatalytic cysteines with chemically tuned electrophiles.  Nature Chemical Biology.  2012 May. 8(5):471-6.
[PubMed]

Shipp L, Lee J, Yu C, Pufall M, Zhang P, Scott D, Wang J.  Transcriptional regulation of human dual specificity protein phosphatase 1 (DUSP1) gene by glucocorticoids.  PloS One.  2010. 5(10):e13754.
[PubMed]

Meijsing S, Pufall M, So A, Bates D, Chen L, Yamamoto K.  DNA binding site sequence directs glucocorticoid receptor structure and activity.  Science (New York, N.Y.).  2009 April. 324(5925):407-10.
[PubMed]

Lee G, Pufall M, Meeker C, Kang H, Graves B, McIntosh L.  The affinity of Ets-1 for DNA is modulated by phosphorylation through transient interactions of an unstructured region.  Journal of Molecular Biology.  2008 October. 382(4):1014-30.
[PubMed]

Pufall M, Lee G, Nelson M, Kang H, Velyvis A, Kay L, McIntosh L, Graves B.  Variable control of Ets-1 DNA binding by multiple phosphates in an unstructured region.  Science (New York, N.Y.).  2005 July. 309(5731):142-5.
[PubMed]

Lee G, Donaldson L, Pufall M, Kang H, Pot I, Graves B, McIntosh L.  The structural and dynamic basis of Ets-1 DNA binding autoinhibition.  The Journal of Biological Chemistry.  2005 February. 280(8):7088-99.
[PubMed]

Garvie C, Pufall M, Graves B, Wolberger C.  Structural analysis of the autoinhibition of Ets-1 and its role in protein partnerships.  The Journal of Biological Chemistry.  2002 November. 277(47):45529-36.
[PubMed]

Pufall M, Graves B.  Autoinhibitory domains: modular effectors of cellular regulation.  Annual Review of Cell and Developmental Biology.  2002. 18:421-62.
[PubMed]

Pufall M, Graves B.  Ets-1 flips for new partner Pax-5.  Structure (London, England : 1993).  2002 January. 10(1):4-Nov.
[PubMed]

Date Last Modified: 06/07/2014 - 21:56:23