A cell's identity and fate are determined by the genes it transcribes. To ensure that gene expression is properly regulated, eukaryotic cells utilize a remarkable amount of protein machinery. Many genes important for cell growth and development are transcriptionally repressed by their packaging into DNA/protein structures called chromatin. In order to activate these genes chromatin is remodeled by the concerted action of sequence-specific DNA-binding transcriptional activator proteins and chromatin remodeling factors. These transcriptional activators also facilitate transcription by recruiting one or more of the `basal' factors necessary for gene transcription. The production of an RNA transcript is also regulated later stages such as transcript elongation, termination, processing, stability and transport. The misregulation of gene transcription can lead to cancer, as many cancer-causing `oncogenes' are known to encode altered forms of transcription factors or chromatin modifying factors. Understanding how oncogenic transcription factors affect cell proliferation is one of the fundamental issues in cancer, and will require a complete understanding of how transcription is normally regulated to know how misregulation occurs.

Several laboratories associated with Huntsman Cancer Institute focus on transcriptional regulation and its connection to cell proliferation and cancer, and provide an excellent environment for graduate study. There are many formalized programs that encourage interaction among students including transcription journal seminar classes, transcription-focused lecture classes, and a weekly transcription journal club. In addition, the institute helps support several core facilities that will assist graduate students in performing cutting-edge research, including DNA microarray, automated DNA sequencing, oligonucleotide and peptide synthesis, flow cytometry, protein interaction (BIACORE), transgenic/targeting, and NMR/mass spectroscopy facilities.

Participating Faculty

Don Ayer - We are interested in networks of transcription factors that heterodimerize to either repress or activate transcription, and in the role of histone acetylation and deacetylation in these processes. We study several transcription factors that play key roles in cell differentiation and proliferation, including Myc, Mad, Mlx, Lef-1 and ß-catenin. We utilize a wide variety of biochemical and molecular techniques in both human cells and model organisms to understand their functions.

Brenda Bass - The Bass laboratory studies a group of RNA editing enzymes called adenosine deaminases that act on RNA (ADARs). ADARs catalyze the conversion of adenosines to inosines within cellular and viral mRNAs so that multiple protein isoforms can be expressed from a single encoded sequence. The laboratory uses C. elegans as a biological system with which to test hypotheses made during in vitro biochemical studies.

Brad Cairns - We are interested in the biology of ATP-dependent chromatin remodeling complexes; including their composition, activities, regulation and targeting. Many genes that play key roles in cell proliferation and differentiation are repressed by chromatin, and are derepressed at the proper time by the action of chromatin remodeling complexes. We combine genetics, biochemistry, molecular biology, and DNA microarray analysis to discover and characterize their functions.

Tim Formosa - Our lab studies the composition and architecture of DNA replication complexes in eukaryotes. Errors in DNA replication lead to genomic instability, so understanding how replication complexes are formed and regulated is a crucial aspect of understanding how genomes are maintained and accurately segregated to progeny. We use a combination of genetics and biochemistry in yeast cells to study interactions among replication components.

Ray Gesteland - The R. Gesteland and J. Atkins joint lab focuses on signals in mRNAs that alter the readout of the code and on using mass spectrometry to understand the proteome - the diversity of protein products from genes. All retroviruses alter the code through frameshifting or codon definition to make reverse transcriptase - clearly many cellular genes will also use these mechanisms to increase their expression diversity. We use genetics and biochemical approaches to study genes with these Signals, including extensive RNA structural probing.

Barbara Graves - We study the ets family of transcription factors, a highly conserved group of proteins that display similar DNA binding properties. In a variety of human cancers, the function of these proteins is perturbed, leading to the dysregulation of gene expression and subsequent loss of control of cell growth. We apply a wide variety of structural and biochemical techniques to understand ets family specificity, specifically testing regulatory pathways that modulate DNA binding activity and protein-protein interactions.

David Jones - Our lab studies the relationships between the control of gene expression and tumor cell responsiveness to chemotherapeutics. Our work aims to define new molecular targets for the development of novel cancer therapies. To accomplish our goals we rely on genomic technologies combined with molecular and cell biology techniques.

Jindrich Kopecek - Design, synthesis, and mechanism of action of macromolecular therapeutics. Attachment of anticancer drugs to polymeric carriers results in an increased accumulation in the tumor tissue, decreased non-specific toxicity, and a different mechanism of action when compared to free drugs. The toxicity, gene expression, and signaling pathways in human ovarian carcinoma models exposed to polymeric drugs are being evaluated in vitro and in vivo. Several conjugates are in clinical trials.

Betty Leibold - We are interested in the pathways by which mammalian cells respond to and adapt to stresses, including metals, oxygen and nitrogen radicals and hypoxia. We are determining the stress-activated signal transduction pathways and genes whose expression is required for survival during stress. We use mammalian cell culture, transgenic mouse models, biochemistry and genetics using C. elegans to determine how organisms survive during stress.

Susan Mango - Our lab is interested in the mechanisms that underlie organogenesis, including cell fate determination and morphogenesis. We study i)how the PHA-4 transcription factor specifies different cell fates within the C. elegans digestive tract during development and ii)how cell shape changes enable a cluster of precursor gut cells to develop into a linear digestive tube. We use genetics, experimental embryology and molecular approaches with C. elegans, a small, free-living nematode. Mango Lab.

Shige Sakonju - We are interested in how spatially restricted expression of homeotic genes is maintained throughout development. Homeotic genes are master regulatory genes that specify body segment identity; their expression patterns must be faithfully maintained to prevent the appearance of homeotic monsters. We use genetic and molecular approaches to study the model organism Drosophila melanogaster.

David Stillman - We are interested in many aspects of transcriptional biology, including how transcription factors help establish or maintain chromatin structures, and how similar transcription factors specifically recognize particular promoters. Chromatin structure and transcription factor binding must be precisely regulated to ensure proper growth and differentiation. We use genetics, molecular biology, and DNA microarray analysis as tools to investigate these processes.

Carl Thummel - The steroid hormone ecdysone exerts dramatic effects on the development of Drosophila melanogaster by triggered cascades of gene activation. Our lab studies how the steroid signal is transduced by members of the nuclear receptor family of transcription factors. In addition, we study the regulation and function of target genes activated by the hormone-receptor complex.

Dennis Winge - We are interested in mechanisms by which cells regulate the intracellular concentration of physiologically important metal ions such as copper, zinc and iron particularly through metal-regulation of gene expression and mechanisms by which cells specifically route metal ions to sites of utilization. Metal ions are essential for most cellular processes and are found in all subcellular compartments, so it is important to understand how cells regulate intracellular levels and route metal ions to organelles. We have focused on yeast as a model eukaryote and use a combination of molecular, genetic and biochemical approaches.

H. Joseph Yost - Our research group is interested in the developmental genetic pathways and mechanisms that establish the vertebrate body plan. We use embryos of zebrafish and the frog Xenopus laevis in complementary approaches, with a focus on how left-right asymmetry is established in the embryo and transmitted to brain, heart and viscera primordial cells. The projects in the lab encompass a broad range of molecular and cell biological topics, including cell-matrix and cell-cell interactions, cell fate and migration, cell signaling pathways from ligand/receptors interactions to transcription co-factors and RNA translational control. Yost Lab.