T-146, Health Sciences Building
Cancer is a complex disease caused by alterations in the expression of genes that normally control cell proliferation, development, and survival. Among the genes that are involved in neoplastic transformation, include a subset called oncogenes. The Iritani lab is studying the Myc oncogene family, of which there are 3 members (c-,N-, and L-Myc). Myc proteins are n to be critical for normal cell division, and their expression are deregulated in many types of cancers including breast, brain, colon cancers, and most leukemias and lymphomas. Myc genes encode for transcription factors that regulate the expression of a yet-defined set of genes that are critical for cell proliferation and growth. Myc proteins bind DNA with a related partner called Max (see figure below). Max can also bind another family of transcription factors called Mad. However, while Myc/Max dimmers stimulate transcription, Mad/Max dimers repress transcription, in part by recruiting a complex of co-repressors including Sin3 and histone deacetylases (HDAC). We are interested in understanding how Myc, and the Mad family of Myc antagonists, normally function in the development and proliferation of lymphocytes, and how these functions are altered during oncogenic activation.
Utilizing cDNA microarray technology, we have identified sets of genes that are increased and decreased by Myc in primary lymphocytes both before and after transformation. We are utilizing gene-targeting, transgenesis, retroviral gene transduction, and chromatin immunoprecipitation to understand which of these genes may be important for the ability of Myc to stimulate cell division and cancer. We are also utilizing lymphocyte-specific transgenic and knockout mice to understand how Myc and Mad normally modulate the development and function of lymphocytes.
Additional studies in the laboratory have focused on utilizing ENU chemical mutagenesis in mice to identify novel genes involved in the development and function of the immune system. In the course of this program, we identified two novel mutant which have mutations in novel genes which regulate immune cell development/function. The first gene called Hem-1 encodes for a hematopoietic cell specific protein called Hematopoietic protein-1, a scaffold protein which is essential for F-actin polymerization and cytoskeletal reorganization in most or all immune cells. Hem-1 null mice exhibit defects in nearly every active process in immune cells including migration, adhesion, and phagocytosis. We are examining the molecular mechanisms behind how Hem-1 controls cytoskeletal reorganization, and whether Hem-1 is important in the invasion of hematopoietic cell cancers. The second mutant we identified encodes for a novel protein we called Fnip1. Fnip1 deficient mice have a complete block in B lymphocyte development at the pre-B cell stage. We hypothesize that Fnip1 functions by regulating cell metabolism during development.
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Fred Hutchison Cancer Research Center | University of Washington
Institute for Systems Biology | Seattle Biomed