Following are descriptions of the lab work done within in the Department of Biochemistry and Molecular Genetics, listed by principal investigator. Learn about the broader goals for study within the labs as well as details on individual faculty labs and teams.
The Structural Basis of Protein Functions
The interactions of proteins with other biological molecules are central features of all biological processes. A molecular understanding of these interactions requires a knowledge of both the three dimensional structures and the biological functions of the molecules involved. Because the most generally applicable method of determining three dimensional structures of biological macromolecules is X-ray crystallography, this technique is central to how we approach biological questions.
A major focus of the lab is in structural genomics. The genome sequencing projects are producing a vast database of sequence information and provide a list of the proteins and their sequences that are used by that organism. The next logical step is to ask what these proteins look like and how they work. This requires developing methods for high throughput structure determination and applying those methods to determine the structures of a large number of target proteins.
A second focus is utilization of the results of the structural genomics effort to expand our understanding of biology. The existence of large databases of protein sequences and structures, combined with the lack of functional characterization of many of those proteins, has reversed the historic pathway leading from function to structure and sequence. Now we need to utilize the sequence and structure information available for proteins to suggest possible functions. The existence of large families of proteins with conserved sequences and structures that are represented in a wide range of organisms but are functionally uncharacterized highlights fundamental areas of biology that are unexplored. Therefore, we are selecting particularly interesting proteins from our structural genomics efforts for further studies of their biological functions.
In addition to providing a library of the most biologically important protein structures, the international structural genomics initiatives provide important information for studies of enzyme mechanisms and the structural basis for catalysis, nucleic acid-protein interactions, protein-protein interactions, and allosteric regulation of protein function. Because the majority of the proteins that have been targeted for structure determination are from bacterial pathogens, the resulting library of structures additionally provide useful starting points for structure guided drug discovery of novel antimicrobials.
For more information, see Dr. Anderson's faculty profile.
Please see Dr. Anderson's publications in PubMed.
Decoding connections between signaling and metabolic networks
The Ben-Sahra lab seeks to identify novel connections between oncogenic and physiological signals and cellular metabolism. My previous studies revealed new connections between mTORC1 (mechanistic Target of Rapamycin Complex I) signaling and de novo nucleotide synthesis pathways.
Using isotopic tracing experiments and genetic approaches, my lab investigates whether the additional signaling pathways such as PI3K/Akt, RAF/Erk, Hippo/Yap or AMPK could regulate metabolic pathways that supply small metabolites to sustain nucleotide synthesis independently of mTORC1 signaling. Furthermore, we are also interested in understanding how cells can sense changes in nucleotide levels. In addition to nucleotide metabolism, we also study connections between signaling pathway and global cancer cell metabolism. I predict that there could be points of regulations which could give selective advantages to cancer cells to grow and proliferate. The initial discovery that cancer cells exhibit atypical metabolic characteristics can be traced to the pioneering work of Otto Warburg, over the first half of the twentieth century.
Deciphering the interplay between oncogenic processes and metabolic pathways that contribute to metabolic reprogramming in a given setting may serve as a critical factor in determining therapeutic targets that yield greatest drug efficacy with marginal harmful effect on normal cells. Our research will enable further progress in the exploitation of unusual metabolic features in cancer as a means of therapeutic intervention.
For lab information and more, see Dr. Ben-Sahra's lab website.
See Dr. Ben-Sahra's publications on PubMed.
Contact Dr. Ben-Sahra.
Studying how the spatial organization of DNA within the nucleus impacts gene expression and chromatin structure.
DNA and proteins are non-randomly localized within the nucleus of the cell. The Brickner lab studies how cells control the position of genes within the nucleus, and how gene positioning affects gene expression. When genes are activated or repressed, their position in the nucleus often changes. The lab has identified DNA "zip codes" in the promoters of genes that control their positioning, transcription and, through an epigenetic mechanism, chromatin structure.
- A conserved role for human Nup98 in altering chromatin structure and promoting epigenetic transcriptional memory. Light WH, Freaney J, Sood V, Thompson A, D'Urso A, Horvath CM, Brickner JH. PLoS Biology. 2013 Mar 26;11(3):e1001524.
- Transcription factor binding to a DNA zip code controls interchromosomal clustering at the nuclear periphery. Brickner DG, Ahmed S, Meldi L, Thompson A, Light W, Young M, Hickman TL, Chu F, Fabre E, Brickner JH. Dev Cell. 2012 Jun 12;22(6):1234-46.
- Interaction of a DNA zip code with the nuclear pore complex promotes H2A.Z incorporation and INO1 transcriptional memory. Light WH, Brickner DG, Brand VR, Brickner JH. Mol Cell. 2010 Oct 8;40(1):112-25.
- DNA zip codes control an ancient mechanism for gene targeting to the nuclear periphery. Ahmed S, Brickner DG, Light WH, Cajigas I, McDonough M, Froyshteter AB, Volpe T, Brickner JH. Nat Cell Biol. 2010 Feb;12(2):111-8.
- H2A.Z-mediated localization of genes at the nuclear periphery confers epigenetic memory of previous transcriptional state. Brickner DG, Cajigas I, Fondufe-Mittendorf Y, Ahmed S, Lee PC, Widom J, Brickner JH. PLoS Biology. 2007 Apr;5(4):e81.
- 2014 Soretta and Henry Shapiro Research Professor in Molecular Biology
- W.M. Keck Young Scholar in Medical Research
- Baldwin Award for Biomedical Research
- Helen Hay Whitney Postdoctoral Fellowship
The Crispino laboratory studies the mechanisms of normal and malignant blood cell growth.
Research in the Crispino laboratory is focused on investigating the regulatory mechanisms governing normal and malignant blood cell development, with an emphasis on understanding the growth of erythroid cells (red blood cells) and megakaryocytes (platelet-producing cells). Major areas of focus include: 1) Understanding the link between Down syndrome and leukemia. We are investigating how mutations in GATA1, a key transcription factor that regulates megakaryocyte growth contribute to leukemia. We are also studying the mechanisms by which trisomy 21 promotes the development of leukemia with a long-term goal of unraveling the mystery of why children with DS are predisposed to leukemia. Our current efforts are focused on characterizing the contributions of two chromosome 21 genes: DYRK1A, a kinase, and ERG, a transcription factor. 2) Development of novel therapeutics for human megakaryocytic malignancies. In collaboration with the Broad Institute, we identified several small molecules that induce proliferation arrest, polyploidization and maturation of malignant megakaryocytes. By a three-pronged target identification approach, we discovered that a key target of these small molecules is Aurora A Kinase. We are currently investigating the utility of AURKA inhibitors as potential new, targeted therapies for acute megakaryocytic leukemia. In addition, we have completed extensive pre-clinical studies to support the testing of AURKA inhibitors in a related blood disease named primary myelofibrosis, a subtype of the MPNs. 3) Investigating the mechanisms of red blood cell development. We are currently studying two aspects of red blood cell development. First, based on our previous discovery that the coalescence of cytoplasmic vesicles is required for enucleation of erythroblasts, we are probing the requirements for specific motor proteins in enucleation and identifying small molecules that enhance enucleation in culture. This research will aid in the development of new strategies to generate red blood cells for transfusion in vitro from stem cells. Second, in line with our expertise and significant interest in GATA1 biology, we are studying the effects of GATA1 mutations on erythropoiesis. We are using state of the art approaches to identify essential, direct GATA1 target genes whose expression depends on the presence of the full-length wild-type protein. This research is relevant to rare red blood cell disorders such as Diamond Blackfan Anemia. Overall, the lab seeks to make seminal basic science discoveries while simultaneously translating these discoveries in ways that will benefit patients with hematologic malignancies.
View lab publications via PubMed.
For more information, visit the faculty profile page of John Crispino, PhD.
Contact Dr. Crispino at 312-503-1504 or the Crispino Lab at 312-503-1433.
Gina Kirsammer, PhD
Research Assistant Professor
Paul Lee, MD, PhD
Pediatric Hematology/Oncology Fellow
Monika Stankiewicz, PhD
Praveen Suraneni, PhD
Benjamin Thompson, MD/PhD
Qiang (Jeremy) Wen, MD/PhD
Research Assistant Professor
Qiong Yang, MD/PhD
Structural Biology, X-ray Crystallography, Macromolecular Structure/Function- GTPase mechanism, Signal Recognition Particle (SRP) targeting complex, and Mitochondrial protein Miro, among others
a. Tetrameric galectin from cynachyrella sp.
b. Hydrogen bonding structure at the N/G domain interface of Ffh.
c. The Ffh/FtsY GTPase heterodimer highlighting its buried nucleotide pair.
We determine the three-dimensional structures of proteins in order to understand the structural basis for and functional mechanisms of interactions between proteins and between proteins and small molecules that play important roles cell biology.
One focus is the GTPases of the Signal Recognition Particle (SRP), Ffh and FtsY. We currently seek to understand the structural basis for regulation of assembly of their heterodimeric targeting complex. The complex is mediated by a remarkable composite GTPase active site, but how this “GTPase core” regulates (and is regulated by) cotranslational targeting remains an important focus of research. Key publication: Focia (2004) Heterodimeric GTPase Core of the SRP Targeting ComplexScience 303 p373-7
We have collaborated with the laboratory of Geoffrey Swanson (Northwestern University, Pharmacology) and Ryuichi Sakai (Hokkaido University) to determine the structure of a novel tetrameric galectin from a marine sponge. Key publication: Freymann (2012) Structure of a tetrameric galectin from Cinachyrella sp.Acta CrystD68 p1163-74
Currently we are collaborating with Sarah Rice (Northwestern University, Cell & Molecular Biology) to understand the mitochondrial protein Miro, a key regulator of Ca-dependent mitochondrial transport. The protein comprises unusually coupled Ca-binding EF hand / GTPase-fold pairs. We seek to determine the structural role for small molecule ligands (i.e. calcium, GTP) in the regulation of this important protein. Key publication: Klosowiak (2013) Structural coupling of the EF hand and C-terminal GTPase domains in the mitochondrial protein MiroEMBO Rep.14 p968-74
We have also initiated a proposal to determine structures of novel members of the bloodstream trypanosome surface coat proteins (VSGs) in order to understand a previously unrecognized minimal structural motif that is widely conserved among unrelated trypanosomal surface proteins.
For more information, visit the faculty profile of Douglas Freymann, PhD.
See Dr. Freymann's publications in PubMed.
Research Assistant Professor:
Pamela FociaStructural Biology Facility Manager, Robert H. Lurie Comprehensive Cancer Center
Mechanisms of signal transmission across the membrane via the cell-surface receptors
This laboratory is interested in cancer, neural development, and reproduction-related structural mechanisms of how extracellular signals (e.g., growth factors, adhesion molecules and morphogens) are translated into intracellular signals by plasma membrane receptors. We use biophysical methods (crystallography, calorimetry, surface plasmon resonance, analytical ultracentrifugation, etc.) in combination with functional studies to define the physiological states and binding processes of these receptors and their complexes with ligands. Our research targets include receptor tyrosine kinases, Semaphorin and its receptors, and leucine-rich-repeat-containing G-protein coupled-receptors.
For more information, visit the faculty profile of Xiaolin He, PhD.
See Dr. He's publications in PubMed.
Contact Dr. He at 312-503-8030 or the He Lab at 312-503-8029.
Structural properties of prion proteins using yeast as a model organism
Prion diseases belong to a class of fatal, infectious neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs), including the bovine spongiform encephalopathies (BSE or mad cow disease) in cattle and Creutzfeldt-Jakob disease (CJD) in human. It is generally accepted that the infectious agent of prion disease is a normal host protein (PrPC) that has adopted a pathogenic conformation that is infectious (PrPSc). Remarkably, there are several atypical yeast proteins capable of existing in multiple stable conformations, each of which is associated with distinct phenotypes. Intriguingly, some of the conformations are able to self-propagate and are “infectious.” They are thus referred to as yeast prions. Our laboratory is interested in study this fascinating prion phenomenon using yeast as a model organism. Yeast offers a powerful system that is amenable to biochemical, cell biological and genetic manipulations. We want to obtain information on the structural properties of yeast prions, their mutual interactions, and their interactions with other cellular factors, particularly, with molecular chaperones. We have recently discovered that the yeast heat-shock transcription factor (HSF), a master regulator of molecular chaperones’ production, plays an important role in governing the de novo formation and “strain” determination of yeast prion [PSI+]. We are working toward to identify novel cellular factors that are HSF targets and important for yeast prion formation and inheritance. The function of HSF is evolutionally conserved from yeast to human. We hope that results from our yeast prion studies will provide valuable information on the complex etiology of the devastating prion diseases.
Our laboratory is also interested in investigating how common the prion phenomenon in biology is. We wish to identify potential prion proteins from yeast and other non-yeast model organisms through a combined approach of bioinformatics and genetic screenings. Our ultimate goal is to uncover the mechanisms governing the prion conformational switch and to understand the biological significance of the protein conformation based prion-like inheritance.
For more information, visit the faculty profile of Liming Li, PhD.
See Dr. Li's publications in PubMed.
Dr. Platanias’ research laboratory focuses on understanding the signaling pathways in different types of cancers in order to develop novel therapies to specifically kill cancer cells.
Cell signaling is part of an intricate system of events activated by various stimuli that coordinate cell responses. Our laboratory is interested in unveiling pathways involved in cancer development in order to target them and control cancer progression. For over two decades, Dr. Platanias’ laboratory has identified several cellular cascades activated by IFN, ATRA and arsenic. Our research on Type I IFN found an essential role for SKAR protein in the regulation of mRNA translation of IFN-sensitive genes and induction of IFN-α biological responses. We also provided evidence for unique function of mTORC2 complex in inducing Type I IFN response. Our studies on arsenic signaling revealed a direct binding of this compound to a kinase called AMPK as a mechanism underlying its anti-leukemic activity. Other work included the activation of biological responses by BCR-ABL oncoprotein through the mTOR pathway. Dr. Platanias’ laboratory is also involved in testing new compounds in combination with approved therapies in order to identify synergy and improve the risk/benefit ratios of current therapeutic regimens for patients.
View lab publications via PubMed.
For more information, visit the faculty profile page of Leonidas Platanias, MD/PhD.
Contact Dr. Platanias at 312-908-5250 or the Platanias Lab at 312-503-4500.
Dirim Arlsan, PhD
Elspeth Beauchamp, PhD
Gavin Timothy Blyth
Post Doctoral Fellow
Research Assistant Professor
Post Doctoral Fellow
Post Doctoral Fellow
Research Assistant Professor
Post Doctoral Fellow
Research Assistant Professor
Molecular machinery for histone modifications in yeast, Drosophila and human cells
Chromosomal rearrangements resulting in alterations of gene expression are a major cause of hematological malignancies. Our goal is to advance the understanding of the biochemical and molecular mechanisms of rearrangement-based leukemia and to provide insights into how translocations affect cellular division by altering gene expression. Using mammalian model systems such as tissue culture and mouse genetics, we plan to explore the regulation of gene expression via the MLL gene and its translocation partners found in human leukemia. We are currently defining the molecular composition of the MLL complexes and how translocations alter its biochemical function and integrity, resulting in leukemic pathogenesis. We are also planning to define the mechanism of the targeting of the MLL complex and its histone methyltransferase activity to chromatin to determine its normal cellular functions and its mistargeting and disregulation in leukemogenesis.
One fusion partner of MLL in acute myelogenous leukemia (AML) is the ELL protein. We show that human ELL functions as a transcription elongation factor. We have identified the Drosophila homolog of ELL and demonstrate it to be essential for development. Drosophila ELL associates with elongating RNA polymerase II in vivo on chromosomes and is a regulator of the Notch signaling pathway. This has suggested to us that human ELL might also participate in the same process.
View Dr. Shilatifard's publications on PubMed.
Molecular Mechanisms of Tumorigenesis and Cancer Metastasis
The Zhang laboratory is focused on two research directions: 1) determining role of tumor suppressors in development and cancer progression, and 2) identifying immune components that control breast cancer metastasis.
The main focus of my research program is to study the roles of tumor suppressors in normal development and in breast and prostate cancer progression, focusing on maspin and an Ets transcription factor PDEF. Maspin is a unique member of the SERPIN family that plays roles in normal tissue development, tumor metastasis, and angiogenesis. Genetic studies by my laboratory using maspin transgenic and knockout mice demonstrated an important role of maspin in normal mammary, prostate, and embryonic development. Recently, we have identified several new properties of maspin. As a protein that is present on cell surface, maspin controls cell-ECM adhesion. This function is responsible for maspin-mediated suppression of tumor cell motility and invasion. We have also discovered that maspin is involved in the induction of tumor cell apoptosis through a mitochondrial death pathway. The long-term goals of these projects are to elucidate the molecular mechanisms by which maspin and PDEF control tumor metastasis and to identify their physiological functions in development. These analyses are not only important for basic biology and but also may lead to a therapy for cancer and other developmental diseases.
Another focus of research in Zhang lab is to identify immune components that control breast cancer metastasis. Chronic inflammation not only increases neoplastic transformation but also drives the inhibition of the immune response in a protective negative-feedback mechanism. Suppressive immune cells are recruited to the sites of inflammation and function to inhibit both innate and adaptive immune responses, enabling tumor tolerance and unmitigated tumor progression. To study the interplay between tumor and immune cells, the Zhang lab has developed a unique animal model of breast cancer that reproduces different stages of breast cancer bone metastasis. Molecules that control tumor-immune cell interaction and immunosuppression have been identified. We are currently studying roles of these genes in tumor-driven evolution that control chronic inflammation and immunosuppression. We hypothesize that these key pro-inflammatory genes are upregulated during cancer progression, which function synergistically to recruit and activate suppressive MDSCs, TAMs and Tregs, inducing chronic inflammation and an immunosuppressive tumor microenvironment conducive to metastatic progression.
For more information visit Ming Zhang's Profile Page.
View publications by Ming Zhang in PubMed