Human BUB Genes: Mitotic Checkpoint Kinases

Developed by:

Background:

Dr. Tim Yen and colleagues of Fox Chase Cancer Center have discovered and characterized human BUB genes that play an important role in the mitotic checkpoint.

The BUB family of serine/threonine kinases is a major target of oncology therapeutic research and development. hBUB1 and hBUBR1 are kinases that associate with hBUB3 and are essential components of the mitotic checkpoint. hBUBR1 appears to provide two checkpoint functions by monitoring CENP-E-dependent activities at the kinetochore and by regulating cyclosome/APC activity.

hBUBR1 is required in order for microtubule inhibitors to arrest cells in mitosis. Non-mutational inactivation of hBUB1 and hBUBR1 appear related to stage of colon cancer and could be related to aneuploidy in human colorectal and other cancers.

Applications:

• Research: This technology is useful for research on mitotic checkpoint mechanisms and for screening. BUB cDNA and oligonucleotides are commonly included as components of microarrays.
• Cancer Drug Discovery: Small molecules able to disrupt regulation or function of BUB proteins have the potential to enhance the effects of anti-tubulin drugs by forcing proliferating cells through mitosis in the absence of a functional mitotic spindle, resulting in damage and cell death.
• A pharmaceutical compound that inhibits Aurora A and Aurora B kinases has been reported to inhibit BUBR1 phosphorylation

Opportunity:

Commercial and research use licenses to intellectual property are available.
Monoclonal antibodies against hBUB and hBUBr1 are also available for licensing.

Publications:

• Wood, KW et al., "Past and future of the mitotic spindle as an oncology target," Curr. Opinion in Pharmacology (2001); 1: 370-377
• Chang, GK et al., "Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC," J Cell Biol. (1999); 146(5): 941-54
• Shichiri, M et al., "Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival," Cancer Res. (2002); 62(1): 13-74
• Chang, GK et al., "Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC," J Cell Biol. (1999); 146(5): 941-54

Patent Status:

Human BUB genes are covered by U.S. Patent 6,593,098 "Genes encoding proteins involved in mitotic checkpoint control and methods of use thereof."