Molecular Biology Research

The Molecular Biology Group at the Department of Radiation Oncology is focusing on the molecular consequences of mutations that lead to uncontrolled gene expression. Cancer is often associated with gain-of-function mutations affecting oncogenes. The c-myc oncogene is frequently overexpressed in human neoplasias. The contribution of c-myc to the development of cancer through its sustained effects on cellular proliferation and differentiation suggests that it may be a good target for the therapy of many types of human malignancies. Indeed, experiments with transgenic mice carried out in other laboratories suggest that the c-myc-induced malignant lymphoid and myeloid tumors regress after inactivation of the c-myc gene.

Alterations in c-myc expression, such as elevated and/or constitutive synthesis of the c-myc RNA occur under a variety of circumstances. For example, the insertion of viral LTR regions near c-myc or translocation of the c-myc gene to chromosomal domains containing strong enhancer activity have been shown to increase steady state levels of c-myc RNA. Transcriptional elongation and promoter-proximal pausing play a pivotal role in the normal regulation of c-myc expression. These mechanisms are crucial in the coordinated regulation of several other genes including the c-fos gene and the HIV-LTR promoter. The long-term goal of our studies is to identify and characterize the function of multi-protein complexes that are responsible for the aberrant regulation of the c-myc gene.

To study the molecular mechanisms that deregulate the expression of the c-myc oncogene, we use different approaches:

I. We are defining the functional and dynamic changes in chromatin structure (e.g. acetylation, phosphorylation and methylation of chromatin compounds) that occur in the course of both normal and aberrant physiologic control of c-myc expression.

II. We are investigating the changes that occur in distant regulatory regulatory elements (e.g. the immunoglobulin heavy chan enhancer) that are involved in the deregulation of the c-myc gene in Burkitt Lymphoma cells.

Based on our previous results, we hypothesize that the post-translational modification of chromatin and the recruitment of factors that both permit the escape of transcription complexes from promoter-proximal sites and increase the RNA chain elongation rate, play an important role in transcriptional enhancement of the c-myc gene. To achieve our goals we have devised a novel approach based on mass spectrometry to characterize enhancer bound components that stimulate transcription. With these studies we hope to contribute to a more detailed understanding of the molecular mechanisms by which distant regulatory elements control tissue and stage specific expression of genes, and the pathways by which deregulation of essential genes results in the pathogenesis of human disease.

This research is funded by the generous support of a Research Scholarship from the American Cancer Society, the Fluorometer Grant Program of Turner Biosystems, and the National Institutes of Health.

Contact:

Anton Krumm, Ph.D.
Department of Radiation Oncology
E-mail: akrumm@u.washington.edu