Under a variety of conditions cells need to grow and many genes support this process. Several of them were discovered by virtue of being mutated and thereby constitutively active in human tumors. As a result, they initially were named oncogenes although their true purpose is, of course, not to cause tumors but to support normal growth. It is only when their expression is aberrant that they cause tumors. Likewise, another set of genes, and the proteins derived from them, provide the counterbalance to the pro-growth genes. Again, this family was discovered in studies of inherited forms of cancer in which the gene had been damaged ("loss of function" mutation). In this case a brake is defective and the accelerator, while set at the normal level, causes the car to go too fast. Again, these genes exist not to suppress tumors but as a counterbalance to normal growth processes. Investigators at Huntsman Cancer Institute have been among the leaders in discovering the existence of tumor suppressor genes and defining their properties. These studies date back more than 15 years and have included findings in areas such as retinoblastoma, neurofibromatosis, and familial polyposis of the colon. Several laboratories in the Institute study both tumor suppressors and oncogenes in projects that seek to understand how specific mutations lead to different types of cancers, how the expression of the genes is controlled, and how the proteins derived from the genes are themselves regulated either at the level of translation or following their synthesis. These topics are covered extensively in the core curriculum for graduate students as well as in several advanced courses for advanced students.

The laboratories that focus these areas have extensive interactions including shared grants - there are two program project grants that strongly emphasize these themes - and a variety of collaborations and other interactions exist. These extend all the way to clinical research and there are several high-risk clinics for patients with inherited cancer syndromes; these subjects serve as an invaluable resource for obtaining samples of DNA and/or tissues for study in a laboratory. In addition to this clinical resource, investigators in this area utilize all of the core resources such as DNA sequencing but particularly emphasize the use of the DNA microarray facility. This facility allows the analysis of global gene expression by assessing the status of several thousand genes in an individual experiment.

Participating Faculty

Donald K. Blumenthal - My laboratory is interested the structure and regulation of protein kinases, especially protein kinases involved in cancer. Protein kinases are key targets for anti-cancer drug development because of their critical roles in many aspects of neoplasia and metastasis. My laboratory employs an integrative approach to studying protein kinases that includes using synthetic peptides and biophysical techniques for structural studies, as well as biochemical and fluorescence techniques to characterize protein kinase activities in vitro and in living cells.

Arthur R. Brothman - My laboratory focuses on the genetic analysis of prostate tumor cells in comparison with clinical outcomes. We evaluate functional genes and genetic sequences that may be altered in prostate cancer. We examine human tissue using cytogenetic, molecular cytogenetic, and molecular biologicial techniques with emphasis on single cell analyses.

Frank Fitzpatrick - Students and post-doctoral fellows investigate the role of inflammation and inflammatory mediators as a risk factor and as host-defense responses against cancer. Scientists working in this laboratory must have a strong commitment to quantitative methodology and a desire to characterize biological processes according to laws of chemistry. Investigations focus on pharmacological mechanisms of modulating tumor suppressor and oncogenic processes, and techniques include chemical and instrumental analysis; cytometric analysis; gene expression analysis.

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.

Douglas Grossman - My laboratory is interested in how apoptosis influences the development and progression of melanoma and nonmelanoma skin cancer. Our initial studies have focused on survivin, a newly recognized inhibitor of apoptosis, that is expressed in basal and squamous cell carcinomas and melanomas, but not in normal keratinocytes or melanocytes. Current experimental approaches include adenoviral-mediated gene transfer, and transgenic and xenograft mouse models.

Linda Kelley - The lab is interested in how the Rb and p53 pathways are disrupted in erythroleukemic transformation resulting from overexpression of the PU.1 oncogene. PU.1 is a member of the ets family of transcriptions factors, which is required for normal development of B cells and monocytes, but causes leukemia when inappropriately regulated in erythrocytes. We use a murine model of virally-induced leukemia to perform genetic and biochemical studies to elucidate oncogenic events associated with leukemic transformation.

Dale Poulter - My laboratory studies the prenylation and endoproteolytic processing reactions of proteins bearing carboxyl-terminal CaaX sequences, where C is cysteine, a is a small aliphatic amino acid, and X is alanine, serine, methionine, or glutamine. Many of these proteins are involved in signal transduction, including the oncogenic Ras proteins that have been implicated in approximately 30% of human cancers. We work on the enzymology of the modifying enzymes, including overexpression in recombinant organisms, site-directed mutagenesis, and purification, and develop inhibitors based on the chemical mechanisms of the reactions.

Steve Prescott - My laboratory is interested in the regulation of cellular events by lipid messengers. This is an area of signal transduction that affects multiple processes in cell growth, differentiation, and motility - all of which are normal processes that have been corrupted in cancer. Our experiments typically utilized cultured cell systems in which the cells have been genetically engineered to express different genes, and the analysis of responses includes techniques in biochemistry, molecular biology, and cell biology.

Wolfram E. Samlowski - My laboratory performs translational research in cancer immunotherapy. We are interested in evaluating mechanisms of cytokine antitumor activity, especially the induction of nitric oxide as a second messenger. Our current studies are evaluating the mechanism of apoptosis induced by nitric oxide, as well as transcriptional regulation of gene expression by this agent. This laboratory uses cell and molecular biology studies, including DNA microarray analysis to evaluate in vitro mechanisms of transcriptional regulation of genes and apoptosis. These observations are then tested in murine cancer models and in human clinical trials.

David Virshup - Protein phosphorylation is the most widely used signal transduction mechanism. We study the role of phosphorylation in the regulation of nucleocytoplasmic transport, circadian rhythm, and the development of cancer, using a combination of biochemical analysis, and tissue culture and animal models.