RESTORATION OF THE TRANSCRIPTION ACTIVATION FUNCTION TO MUTANT P53 INHUMAN CANCER-CELLS

The p53 tumor suppressor gene product is a sequence-specific transcrip tion activator frequently mutated in a variety of human malignancies. Typically, tumor-derived p53 missense mutants are defective in DNA bin ding and this is likely to result in a failure to active p53-regulated genes. Hence, restoring function to mutant p53 represents an attracti ve target to develop a novel cancer chemotherapeutic agent. We now sho w that a small chemically modified peptide derived from p53 restores s equence-specific DNA binding to a subset of p53 mutants. Moreover, whe n microinjected into human colon carcinoma cells this peptide restores the transcription activation function to endogenous mutant p53 protei n. This is the first example showing that a small peptide molecule can reverse the effect of several inactivating missense mutations and res tore protein function.