Research in this laboratory focuses on the control of cell division cycles in development and disease. We are particularly interested in how the cell cycle checkpoints are activated in response to internal and external stimuli and what are the consequences should these checkpoints fail.
Control of Cell Proliferation
Cellular proliferation is controlled by cyclin-dependent kinases whose activities are absolutely required for cell cycle progression. Cdks are regulated positively by cyclins and negatively by Cdk inhibitors (CKIs). Loss of cell cycle control is the underlying mechanisms of tumor development and causes congenital birth defects due to problems incurred during embryonic development. There are two very important control points during cell cycle. One is the G1 to S transition where cells decide whether to commit themselves to another round of division or to take a different developmental fate. The other is mitosis when the duplicated genome is equally partitioned to two daughter cells. Errors in this process leads to gain/loss of chromosomes, or chromosomal instability, a potential driving force in tumorigenesis.
The major deficit in the research area of cell cycle control and development is that we do not know how the cell cycle control is linked to developmental programs. We believe that cyclins and CKIs provide the link. One research direction of this lab is to take molecular and genetic approaches to understand how proliferation/differentiation signals are transduced to the cell cycle control machinery. We are taking p57KIP2, a CKI an example. Although the pathways that can activate p57KIP2 are still being sought after, we have found that the expression of this Cdk inhibitor is suppressed by the Notch signaling pathway, an ancient developmental pathway involved in the maintenance of progenitor cells.
Genome Instability and Tumorigenesis
Another direction we are taking is using genetic engineered mouse models to dissect the spindle assembly checkpoint and its role in preventing chromosome instability (CIN). CIN can be numerical changes in whole chromosomes (aneuploidy) or structural alterations such as translocations. Aneuploidy is found in nearly all of the major human tumor types and it was the abnormal chromosome numbers in cancerous cells that prompted Boveri to propose nearly a century ago that cancer was caused by aneuploidy. The most important cellular mechanism that prevents aneuploidy is the spindle assembly checkpoint (SAC). SAC is activated when kinetochores are not attached (i.e. occupied) by microtubules and/or when there is a lack of tension at sister kinetochores under both of which situations separation of sister chromatids needs to be actively prevented or missegregation of chromosomes would ensue. Nearly all SAC-compromised mouse strains develop spontaneous tumors, although the rates vary substantially.
Together with the finding of BUBR1 mutation in mosaic variegated aneuploidy, a condition that predisposes patients to childhood cancers, the tumor results in SAC mutants strongly argue that aneuploidy can induce tumorigenesis. However, the spontaneous tumor development in SAC mutant mice is usually late onset and at relatively low rates, suggesting that there are limiting factors. We have now identified at least one such limiting factor and genome-wide screens are underway to identify genes whose loss or gain of function can cooperate with aneuploidy in driving oncogenic transformation.
Control of Growth, Metabolism and Obesity
A third direction we are taking is to understand the control of growth, metabolism and obesity (after all, the lab is homed in the physiology department). Obesity is becoming a major health issue worldwide. Working on a newly-identified obesity-associated gene, FTO, we are gaining insights into a new kind of regulation of gene expression. FTO is predicted to be a ssDNA or ssRNA demethylase but its physiological substrates are unknown. Our mouse genetic results suggest that FTO functions in the hypothalamus-pituitary axis. Future work is centered on identify FTO targets.
In summary, we are taking all available technologies to probe issues not only important in basic biology but also have clinical ramifications.