SIAU Jia Wei

Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket

Published date : 15 Jan 2019

The DNA binding domain (DBD) of the tumor suppressor p53 is the site of several oncogenic mutations. A subset of these mutations lowers the unfolding temperature of the DBD. Unfolding leads to the exposure of a hydrophobic β-strand and nucleates aggregation which results in pathologies through loss of function and dominant negative/gain of function effects.

type
Journal Paper
journal
Nuclei Acids Research, 2019, doi: 10.1093/nar/gky1314
Impact Factor
11.561

Functional characterization of p53 pathway components in the ancient metazoan Trichoplax adhaerens

Published date : 28 Sep 2016

The identification of genes encoding a p53 family member and an Mdm2 ortholog in the ancient placozoan Trichoplax adhaerens advocates for the evolutionary conservation of a pivotal stress-response pathway observed in all higher eukaryotes. Here, we recapitulate several key functionalities ascribed to this known interacting protein pair by analysis of the placozoan proteins (Tap53 and TaMdm2) using both in vitro and cellular assays.

type
Journal Paper
journal
Scientific Report 6, 33972, 2016, doi:10.1038/srep33972

Avoiding drug resistance through extended drug target interfaces: a case for stapled peptides

Published date : 04 Apr 2016

Cancer drugs often fail due to the emergence of clinical resistance. This can manifest through mutations in target proteins that selectively exclude drug binding whilst retaining aberrant function. A priori knowledge of resistance-inducing mutations is therefore important for both drug design and clinical surveillance. Stapled peptides represent a novel class of antagonists capable of inhibiting therapeutically relevant protein-protein interactions. Here, we address the important question of potential resistance to stapled peptide inhibitors.

type
Journal Paper
journal
Oncotarget. 2016 Apr 4. doi: 10.18632/oncotarget.8572
Impact Factor
5.008

The p53-Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans

Published date : 21 Jan 2016

The extant jawless vertebrates, represented by lampreys and hagfish, are the oldest group of vertebrates and provide an interesting genomic evolutionary pivot point between invertebrates and jawed vertebrates. Through genome analysis of one of these jawless vertebrates, the Japanese lamprey (Lethenteron japonicum), we identified all three members of the important p53 transcription factor family-Tp53, Tp63, and Tp73-as well as the Mdm2 and Mdm4 genes.

type
Journal Paper
journal
Genes & Development 2016 Feb 1;30(3):281-92. doi: 10.1101/gad.274118.115
Impact Factor
10.798

Inhibition of Nutlin-Resistant HDM2 Mutants by Stapled Peptides

Published date : 20 Nov 2013

Pharmacological modulation of p53 activity is an attractive therapeutic strategy in cancers with wild-type p53. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2, a key negative regulator of p53 and blocks its activity. We have described resistance mutations in HDM2 that selectively reduce affinity for Nutlin but not p53.

type
Journal Paper
journal
PLoS One, November 2013, Vol. 8, Issue 11, doi:10.1371/journal.pone.0081068
Impact Factor
3.73

Binding of Translationally Controlled Tumour Protein to the N-terminal domain of HDM2 is inhibited by Nutlin-3

Published date : 13 Aug 2012

Translationally Controlled Tumour Protein (TCTP), a highly conserved protein present in all eukaryotic organisms, has a number of intracellular and extracellular functions including an anti-apoptotic role. TCTP was recently shown to interact with both p53 and HDM2, inhibiting auto-ubiquitination of the latter and thereby promoting p53 degradation. In this study, we further investigated the interaction between TCTP and HDM2, mapping the reciprocal binding sites of TCTP and HDM2. TCTP primarily interacts with the N-terminal, p53-binding region of HDM2 through its highly basic domain 2.

type
Journal Paper
journal
PLoS One 2012, Vol 7, Issue 8, doi: 10.1371/journal.pone.0042642