Princeton University
Invention # 2174
Cancer is one of the most debilitating diseases affecting mankind. More
than 600 thousand patients die of cancer in the United States. Oncogenesis is
inhibited by the tumor suppressor genes and accelerated by oncogenes. p53 is one
of the most important tumor suppressor proteins and is inactivated in nearly all
cases of cancer. In approximately half of all cancer cases, p53 is inactivated
by mutation; in the other half of all cancer cases, wild-type p53 is inactivated
by accelerated degradation or mis-localization, thus unable to perform its
function. MDM2 is an oncoprotein that actively ubiquinates p53, leading to its
degradation. MDM2 also ubigquinates itself, thus resulting in its own
degradation. Restoration of p53 function in cancer patients constitutes an
important and effective therapeutic method.
HAUSP is a member of the UBP family of deubiquinating enzymes and
selectively targets MDM2 and p53 for deubiquination, hence rescuing both
proteins from degradation. The specific deubiquination relies on the specific
binding of MDM2 and p53 by HAUSP.
Researchers at Princeton University have discovered that HAUSP exhibits a
much higher binding affinity for MDM2 than for p53, implying that MDM2 is a bona
fide substrate for HAUSP in cells. More importantly, the group at Princeton has
discovered that both MDM2 and p53 bind to the same surface pocket in the
amino-terminal TRAF-like domain of HAUSP in a mutually exclusive manner.
The binding element from MDM2 or p53 is a short peptide composed of no more than
6 amino acids. In addition, a number of crystal structures on HAUSP, including
the catalytic core domain, the catalytic core domain bound to ubiquitin
aldehyde, the N-terminal TRAF-like domain, the N-terminal TRAF-like domain bound
to MDM2 peptide, the N-terminal TRAF-like domain bound to p53 peptide, and the
combined TRAF-like and catalytic core domain have been determined at
Princeton. These structures reveal important insights on inhibitor
screening. In particular, the TRAF-like domain contains a surface groove that is
responsible for binding to the MDM2 or p53 peptide. The catalytic core domain
contains a papain-like active site. The carboxy-terminus of ubiquitin is
specifically coordinated by a surface cleft in the catalytic core
domain.
These novel findings immediately identify methods for the screening of
anti-HAUSP compounds that will serve to stabilize p53 protein by destabilizing
the human MDM2 protein.
The
first method involves screening for compounds that bind to the surface groove of
the TRAF-like domain. These compounds will prevent the specific recognition for
MDM2 by HAUSP, hence accelerating the degradation of MDM2. The second method
involves screening for compounds that bind to the surface cleft of the catalytic
core domain, which normally coordinates the carboxy-terminus of ubiquitin. These
compounds will interfere with the deubiquinating activity of HAUSP. The third
method involves screening for compounds that directly bind to the active site of
HAUSP, hence suppressing its catalytic activity.
Princeton is currently seeking industrial collaboration to commercialize
this technology. Patent protection is pending.
Publications;
HU,M., Li,P., Li,M.,
Li,W., Yao,T., Wu,J., Gu,W., Cohen,R., Shi,Y., December 27, 2002, Crystal
Structure of a UBP-Family Deubiquinationg Enzyme in Isolation and in Complex
with Ubiquitin Aldehyde, Cell, , Vol. 111,
1041-1054.
Structural Basis of
Competitive Recognition of p53 and MDM2 by HAUSP/USP7, Hu,M., Gu,L., Jeffrey,P.,
Shi,Y., Pending Publication
For more information on
Princeton University invention # 05-2174 contact:
Laurie Tzodikov
Office of Technology Licensing and Intellectual
Property
Princeton University
4 New South Building
Princeton, NJ 08544-0036
(609) 258-7256
(609) 258-1159 fax
tzodikov@princeton.edu