Correct cell cycle regulation is essential to prevent carcinogenesis. Mis-regulation of the cell cycle can allow uncontrolled growth and division. Mis-regulation can also cause genome instability which generates genetic changes which can further facilitate uncontrolled proliferation and may promote metastasis.
Many medical and biological problems center around the control of cell division. Cancer cells divide persistently when they should not; wound healing depends on rapid but controlled cell division; aging is partly a problem of cells that become unable to divide at all. The main interest in our lab is understanding the basic mechanism that controls cell division. This mechanism is surprisingly similar in all eukaryotes, from yeast to humans. It involves a family of unstable proteins called cyclins, which bind to and activate a protein kinase called cdc2. The abundance of cyclins is regulated by a variety of cellular and environmental conditions, and it helps determine whether cdc2 will be activated. One cyclin family works at the "commitment point" for cell division in the G1 (growth) phase of the cell cycle, whereas a second group of cyclins works at the M (mitosis) phase.
While cancer is the result of too much division, aging is (in part) the result of too little division. Normal mammalian cells can go through only a limited number of divisions. The number of divisions remaining to a cell correlates with the length of the repetitive DNA at the very ends of the chromosomes, the telomeres. Cells with short telomeres can go through only a few divisions. We are trying to see whether loss of telomeric DNA is the direct cause of cellular senescence.
Our work with the yeast cell cycle has led us to the use of microarrays for genome-wide assays of gene expression. Computer analysis of the results has uncovered a regulatory network involving clusters of genes. Each cluster turns on the next cluster, and turns off the previous cluster, until the circle is complete. A combination of traditional molecular biology and yeast genetics, microarray analysis, and computer analysis is helping to outline the molecular mechanisms by which transcription of about 800 cell cycle regulated genes is controlled.