My laboratory is interested in the molecular basis of human cancer. Our approach is to study the normal and malignant functions of genes implicated in human cancer at the level of the cell and the entire organism.
Specific research topics:
Mitotic checkpoint function and chromosomal stability. We are interested in some of the basic molecular mechanisms that regulate chromosome number stability in mammalian cells. Our understanding of these mechanisms is relevant as abnormalities of chromosome number are a hallmark of the vast majority of human cancers. A subset of these cancers is associated with mutations in genes encoding for mitotic checkpoint proteins, such as Bub1, BubR1, Bub3 or Mad2. These checkpoint proteins are part of an intricate regulatory mechanism that prevents aneuploidy by delaying sister chromatid separation until all chromosomes are properly attached to the mitotic spindle apparatus and aligned at the metaphase plate.
The major objective of our work is to understand the role of distinct mitotic checkpoint proteins in normal and neoplastic growth. Much of our work utilizes genetically engineered mice in which individual mitotic checkpoint genes have been mutated, but we also address several basic questions of mitotic checkpoint regulation using somatic tissue culture cells.
Recently, we found that the nucleoporin Nup98 contains a motif, termed GLEBS that directs binding to the putative mRNA export factor Rae1. Interestingly, GLEBS motifs are also present in the mitotic checkpoint proteins Bub1 and BubR1, where they serve as binding sites for the Rae1-related mitotic checkpoint protein Bub3. These findings have prompted us to test whether Nup98 and Rae1 function in both transport of macromolecules into and out of the nucleus through nuclear pores and segregation of chromosomes during mitosis.
Transcriptional coactivators in normal and neoplastic growth. Another major objective of our work is to understand the role of CBP and p300 in normal and malignant cell growth. CBP and p300 are highly related transcriptional coactivators that seem to modulate the functions of a wide variety of transcription factors. Recent studies have provided genetic evidence that CBP and p300 could act as tumor suppressor genes in a variety of human tissues, including breast, colon and lung. One idea is that loss of CBP or p300 function could simply lead to derailment of factors that are required for the proper control of cell growth, differentiation and death. The simplest way to demonstrate the tumor suppressor activity of CBP and p300 would be to genetically disrupt their genetic loci in the mouse and monitor the resulting animals for tumor formation. However, both CBP and p300 are essential for growth and development, and cause similar embryonically lethal phenotypes when completely disrupted in the mouse.
We are trying to bypass this problem using CBP and p300 conditional knockout mice. Our emphasis is to test whether disruption of CBP and p300 in intestinal and mammary gland epithelium leads to tumor formation.