Timothy J. Ley, M.D. (Director)

DEPARTMENT OF Internal Medicine
Jeffrey D. Milbrandt, M.D., Ph.D.; Thomas F. Deuel, M.D.
Keywords: immunology, genetics, molecular biology, cell biology

The long-range goals of this program are to elucidate and characterize basic mechanisms that regulate growth-related and developmentally-related genes as they are normally expressed or inappropriately expressed in neoplastic cells.

Cancer can be characterized by the dysregulated growth of cells which phenotypically fail to recapitulate normal differentiation and development. It may also result from a failure of programmed (apoptotic) cell death. In our program we study the normal and abnormal regulation of growth and development through analyses of separate, highly related, genetically regulated pathways. We analyze the sequences and interactive proteins that regulate essential genes within these pathways, the loss and gain of proteins that regulate other essential genes within these pathways that may in turn lead to abnormal growth and the loss and gain of function of these genes in mice and embryonic stem cells.

The strategy common to each of the program’s component projects extends from an in-depth analysis of the regulation of transcription of these genes and regulatory elements to a modification of lineage- and temporal-specific expression of growth and development by introduction of the genes into cells, transgenic mice and loss-of-function mice through targeted disruption of these genes. It is our hope that an understanding of these normal and abnormal regulatory mechanisms will lead to logical approaches to the treatment of neoplastic disease in man.

We focus on growth factor genes, genes that appear to direct differentiation functions, genes that function to prevent cell death, genes that encode transcription factors that are activated by growth factors (and that direct nuclear signals to program growth factor signals) and highly developmentally-regulated genes that are expressed in a lineage-specific manner. We use the tools of molecular biology, cell biology, biochemistry and immunology, cDNA and genomic cloning, DNA sequencing, identification of cis-acting elements, identification and purification of trans-acting transcriptional proteins, transcriptional analyses, in situ hybridization and immunoperoxidase analyses. Both gain- and loss-of-function experiments in the transgenic mouse and in heterozygous and homozygously targeted loss-of-function mice are employed.