Rescue of the p53 tumor suppressor by a rationally designed molecule.
Extract: The tumor suppressor protein p53 is crucial in preventing cancer as well as for achieving the therapeutic effects of both radiotherapy and much of chemotherapy. p53 responds to oncogene activation, DNA damage, hypoxia and other stresses by activating the expression of factors that trigger cell cycle arrest or programmed cell death. Strong evidence that inactivation of p53 is required for cancer cell survival comes from accumulated data that p53 is inactivated by mutations in some 50% of all human tumors, regardless of patient age or tumor type. This makes p53 the most frequently mutated gene in cancer, with more than 18,000 mutations reported so far. Most of the mutations result in a substitution of just one amino acid residue in the core DNA binding domain of p53, which frequently causes the protein to "melt" or denature at body temperature, and thus abolishes its function. Given the high potency of p53 in the induction of cell death, it is expected that small molecules that can refold p53 and rescue its function will efficiently and selectively kill tumor cells, thus providing a powerful new way to combat cancer. Notably, the accumulation of high levels of mutant p53 in tumor cells allows for a selective targeting of tumors.
Selivanova
Galina
G
Karolinska Institutet, Microbiology and Tumor Biology Center (MTC), Box 280, SE-171 77 Stockholm, Sweden.
Fersht
Alan
A