PI: Susan M. Mendrysa, Ph.D., Purdue University
First year, August 2011- September 2012, Funding duration 2011-2013
Medulloblastoma (MB) is the most common malignant brain cancer of childhood. Although mutations in the p53 tumor suppressor protein are found in the majority of human cancer, p53 mutations are rare in MB tumors. This suggests that alternative events or signaling pathways may inhibit the function of p53 in MB. Our goal is to understand how p53 function is limited in MB. Toward this goal, we have found that MDM2, a protein which normally inhibits p53 function, is regulated by the Sonic Hedgehog pathway, a pathway known to be critical during cerebellar development, and which is aberrantly activated in >25% of human MB tumors. Our findings therefore place MDM2 at the nexus between the p53 and Sonic Hedgehog signaling pathways. Our current research aims to determine the mechanism(s) by which MDM2 activity coordinates the opposing physiologic outcomes of the p53 and Sonic Hedgehog pathways in cerebellar progenitor cells in order to improve our understanding of MB pathogenesis. New knowledge of MB pathogenesis is will serve as a critical step toward the development of more selective therapeutics for the treatment of MB.