Download Molecular Mechanism of Mutant p53 Stabilization

Molecular Mechanism of Mutant p53 Stabilization: The Role of HSP70 and MDM2
Wiech M, Olszewski MB, Tracz-Gaszewska Z, Wawrzynow B, Zylicz M, et al.
PLoS ONE 7(12): e51426.
Presenter: Pang-Yi Teng
Commentator: Li-Tzong Chen, M.D., Ph.D
December 12, 2012.
Date/Time: 2013/06/20 16:10-17:00
Location: Room 602, Med College Building
Background:
Mutations in p53 tumor suppressor gene were identified in most human cancers. More than 70% of these
mutations are missense and mostly gain new pro-oncogenic functions. The molecular mechanisms about
the pro-oncogenic functions are still not clear. In normal unstressed cells, wild-type p53 protein is regulated
by MDM2 E3 ubiquitin ligases. In 2011, Dun Li et al. report that HSP90 inactivates MDM2 and CHIP
(C-terminus of HSC70-Interacting Protein) ubiquitination in cancer cells harbouring mutant p53, thus
impairing degradation of mutant p53. In addition, mutated p53 also found to form a stable complex with
HSP40 and HSP70. These aggregation complexes may contribute to p53 stabilization.
Objective/Hypothesis:
The formation of HSP70- and MDM2-dependent protein aggregates in tumors could be one of the
mechanisms by which mutant p53 is stabilized.
Results:
Using non-cancerous embryonic fibroblasts (MEFs) from double knockout mice (Trp53-/- and Mdm2-/-)
transfected plasmid encoding p53 R175H, MDM2 and different members of HSPA family chaperones
(HSP70, HSC 70 and HSP 70 K71S) find that overexpression of HSP70 inhibits MDM2-dependent ubiquitination of p53 R175H and results in cytoplasmic pseudo-aggregates. In the presence of HSP70 and MDM2,
these pseudo-aggregates form stable amyloid-like structures, which colocalize with p53 R175H in an
aggressome. This phenomenon is not observed in the presence of HSC70, HSP70 K71S or treatment with
HSP70 inhibitor, suggest that mutant p53 spots are folding intermediates triggered by active HSP70.
Refolding kinetics of p53 indicate that HSP70 causes transient exposure of p53 aggregate-prone domain(s).
Moreover, the p53 paralog- p73 tumor suppressor protein is sequestrated by p53 R175H. These
aggregations may lead to gain-of function phenotypes.
Conclusion:
These data suggest that the pro-oncogenic, gain-of-function phenotype of mutant p53 is governed by
HSP70 and MDM2 levels. And may provide a new therapeutic approach, whereby specific HSP70 inhibitors
could be used synergistically treatment of patients with mutated p53.
Reference:
1.Dun Li, Natalia D. Marchenko, Ramona Schulz, et al. Functional Inactivation of Endogenous MDM2 and
CHIP by HSP90 Causes Aberrant Stabilization of Mutant p53 in Human Cancer Cells. Mol Cancer Res
2011;9:577-588.