Research at Fox Chase »Technology Transfer »Technology Licensing

« Technology Licensing

Description

Dr. Maureen Murphy and colleagues at Fox Chase Cancer Center have identified repression elements in the promoters of two p53repressed genes, Survivin 1 and MAP4 2. These elements are the first nucleotide sequences that are sufficient to confer transcriptional repression by p53 to heterologous genes, even when the genes are integrated into chromatin. The presence of these elements in promoter regions results in greater than tenfold repression of heterologous genes by p53.

The p53 tumor suppressor protein plays a major role in the death of abnormal cells through cellcycle arrest and programmed cell death (apoptosis). The p53 gene has been found to be inactivated in approximately sixty percent of human tumors, resulting in the survival and growth of cancer cells.

MAP4 is a microtubuleassociated protein that regulates the assembly of microtubules, enabling cell division. Survivin is an "inhibitor of apoptosis" (IAP) that prevents cell death by apoptosis. It is expressed at very low levels in normal cells but is overexpressed in cancer cells. 3 In normal cells, p53 protein binds to elements in the promoters of Survivin and MAP4, repressing gene expression. Inactivation of p53 in cancer cells results in uncontrolled expression of Survivin and MAP4 and the survival and growth of cancer cells. Dr. Murphy and colleagues have identified and sequenced these p53 repression elements.

Applications

• Research: The p53 repression elements are useful in studies on p53 and transcriptional repression of Map4, survivin, and other p53repressed genes.
• Cancer Drug Discovery: The repression elements can be used as drugscreening tools to identify agents that will either promote or inhibit p53mediated repression of target genes.
• Gene Therapy: The elements can be used to selectively target cells (such as cancer cells) that contain inactivated p53 by gene therapy. For instance, a p53 repression element can be inserted in the promoter region of a cytotoxic gene and delivered via a vector. Only those cells containing inactivated p53 will express the gene and be killed by the toxin; normal cells will be spared.

Publications

• Hoffman, WH et al., "Transcriptional repression of the antiapoptotic survivin gene by wild type p53," J. Biol. Chem. (2002); 277: 3247-57
• Murphy, M 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
• Bao, R et al., "Activation of cancerspecific gene expression by the survivin promoter," JNCI (2002); 94: 522-8

Patent Status

U.S Patent 7,053,194: "Compositions and methods for p53-mediated repression of gene expression"

For more information, contact

Clarissa Ceruti, PhD, MBA
Associate Director, Office of Corporate Alliances
Fox Chase Cancer Center
610 Old York Road, Room 407
Jenkintown, PA 19046
Tel.: 215-214-1546
Fax: 215-214-1440
clarissa.ceruti@fccc.edu