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Methods for stabilization of mP53 in embryonic stem cells for cancer treatment

Technology Number: 

1745
Summary 

Cancer is a leading cause of death in the developed countries. It is a highly heterogeneous disease even among patients with the same type and grade of cancer. Thus, drug development for cancer is extremely challenging. However there are some consistencies; most tumor cells exhibit genomic instability with an increased expression of oncogenes and inactivation of tumor suppressor genes.
P53 is a key tumor suppressor that is mutated in more than half of the human cancers. Over the years several mouse models were developed in order to study p53 mutations. Interestingly it has been shown that mice homozygous for mutant p53 are viable, and develop malignant tumors only in adulthood.
Prof. Rotter and her team revealed the mechanism by which embryos are protected from mutant p53-induced transformation. They found, using embryos stem cells (ESCs), that the conformation of mutant p53 in ESCs is stabilized to a WT conformation. They further identified the network of proteins that may shift p53 transformation to its WT form.
This technology presents methods (compositions and kits) of stabilizing mutant p53 in ESCs by interacting proteins, thus propose a novel cancer therapy.

Applications


  • Cancer

Advantages


  • Targeted for p53
  • Safe

Technology's Essence


The researchers  hypothesized that cellular factors in the pluripotent cells contribute the stabilization of the WT conformation of p53. They used a mass spectrometry (MS)-based interactome analysis to examind the interaction network of the different conformations of p53 in WT and Mut ESCs compared with somatic cells from the spleen. They immunoprecipitated WT and Mut conformation of p53 and used p53 KO cells as controls for background binding. Importantly, they identifies chromatic-specific proteomic network that is suggested to bind p53 and act as a stabilizer of Mut p53 into a WT conformation. This network (59 proteins) includes the CCT complex, USP7, Aurora kinase, Nedd4, and trim24. Interactions with this network enables the activation of WT activity of p53 and eliminates the gain-of function Mut activities, despite the p53 mutation.
Overall this is a proposed mechanism of rescuing ESCs cells from transformation which sets the basis for future p53-targeted cancer therapeutics. 

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