Vanessa Lopez-Pajares
Yuan Laboratory
Harvard School of Public Health
As
a member of the Yuan lab, I am interested in researching the regulation
of the p53 tumor suppressor. p53 is a transcription factor whose gene is
mutated in over 50% of cancers. As a tumor suppressor, it is a key regulator
of the cell cycle. Activation of p53 in response to cellular stresses, such
as DNA damage, leads to cell cycle arrest or apoptosis. Because p53 is such
a potent inhibitor of cell cycle progression, its activity is tightly regulated,
particularly at the protein level. An important regulator of p53 is MDM2,
a protein which has an E3 ligase activity and targets p53 for ubiquitin-mediated
proteasomal degradation. MDM2 and p53 exist in a negative feedback loop
whereby p53 activates the transcription of the mdm2 gene to maintain low
levels of p53 protein under normal cellular conditions. MDMX is a recently
identified homologue of MDM2, which also plays a critical role in the regulation
of p53, although it lacks an E3 ligase activity. Deletion of either MDM2
or MDMX results in p53-dependent embryonic lethality in mice, suggesting
these two proteins play non-redundant roles. Studies in our laboratory have
demonstrated that MDM2 and MDMX are functionally dependent on each other
to inhibit p53 activity. My current research focuses on identifying molecules
and signaling pathways that can regulate MDMX and in turn regulate p53.