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1.  ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis 
Cell Death and Differentiation  2014;21(4):612-623.
Rescue of the p53 tumor suppressor is an attractive cancer therapy approach. However, pharmacologically activated p53 can induce diverse responses ranging from cell death to growth arrest and DNA repair, which limits the efficient application of p53-reactivating drugs in clinic. Elucidation of the molecular mechanisms defining the biological outcome upon p53 activation remains a grand challenge in the p53 field. Here, we report that concurrent pharmacological activation of p53 and inhibition of thioredoxin reductase followed by generation of reactive oxygen species (ROS), result in the synthetic lethality in cancer cells. ROS promote the activation of c-Jun N-terminal kinase (JNK) and DNA damage response, which establishes a positive feedback loop with p53. This converts the p53-induced growth arrest/senescence to apoptosis. We identified several survival oncogenes inhibited by p53 in JNK-dependent manner, including Mcl1, PI3K, eIF4E, as well as p53 inhibitors Wip1 and MdmX. Further, we show that Wip1 is one of the crucial executors downstream of JNK whose ablation confers the enhanced and sustained p53 transcriptional response contributing to cell death. Our study provides novel insights for manipulating p53 response in a controlled way. Further, our results may enable new pharmacological strategy to exploit abnormally high ROS level, often linked with higher aggressiveness in cancer, to selectively kill cancer cells upon pharmacological reactivation of p53.
PMCID: PMC3950324  PMID: 24413150
TrxR; ROS; JNK; p53; Wip1; inhibition of oncogenes
2.  3DTF: a web server for predicting transcription factor PWMs using 3D structure-based energy calculations 
Nucleic Acids Research  2012;40(Web Server issue):W180-W185.
We present the webserver 3D transcription factor (3DTF) to compute position-specific weight matrices (PWMs) of transcription factors using a knowledge-based statistical potential derived from crystallographic data on protein–DNA complexes. Analysis of available structures that can be used to construct PWMs shows that there are hundreds of 3D structures from which PWMs could be derived, as well as thousands of proteins homologous to these. Therefore, we created 3DTF, which delivers binding matrices given the experimental or modeled protein–DNA complex. The webserver can be used by biologists to derive novel PWMs for transcription factors lacking known binding sites and is freely accessible at
PMCID: PMC3394331  PMID: 22693215
3.  ProSAT2—Protein Structure Annotation Server 
Nucleic Acids Research  2006;34(Web Server issue):W79-W83.
ProSAT2 is a server to facilitate interactive visualization of sequence-based, residue-specific annotations mapped onto 3D protein structures. As the successor of ProSAT (Protein Structure Annotation Tool), it includes its features for visualizing SwissProt and PROSITE functional annotations. Currently, the ProSAT2 server can perform automated mapping of information on variants and mutations from the UniProt KnowledgeBase and the BRENDA enzyme information system onto protein structures. It also accepts and maps user-prepared annotations. By means of an annotation selector, the user can interactively select and group residue-based information according to criteria such as whether a mutation affects enzyme activity. The visualization of the protein structures is based on the WebMol Java molecular viewer and permits simultaneous highlighting of annotated residues and viewing of the corresponding descriptive texts. ProSAT2 is available at .
PMCID: PMC1538895  PMID: 16845114

Results 1-3 (3)