Zambetti: Function of p53 in tumor suppression and tumorigenesis

The p53 tumor suppressor is the most frequently mutated gene detected in human cancer. Wild-type p53 acts as a safeguard against cancer by regulating the expression of a series of genes that mediate cell cycle arrest or apoptosis. Identification of these p53-target genes and the factors that regulate p53 function is essential to understanding tumorigenesis.

We are currently studying EI24, which is a novel, p53-regulated gene that is highly conserved throughout evolution. The EI24 gene is localized to a region of DNA which is involved in breast cancer, malignant melanoma, and invasive cervical cancer. We are applying molecular, cellular and gene knockout approaches in order to determine its function and possible role in tumorigenesis.

Certain cytokines inhibit wild-type p53-mediated programmed cell death. We are characterizing the signaling pathways that suppress cell death following DNA damage using biochemical approaches and cell lines expressing cytokine receptor mutants. We are also studying cytokine signaling pathways that regulate cell cycle progression following DNA damage.

Mutant p53 enhances tumorigenicity and this tumor promoting function correlates with its ability to transactivate the multi-drug resistance (MDR) promoter. Our results from promoter mapping and p53 protein structure-function analyses suggest that mutant p53 may enhance gene expression through an RNA-dependent mechanism that may be similar to the model proposed for HIV LTR regulation. Defining the mechanism by which mutant p53 promotes transactivation may lead to therapies that reduce the tumorigenicity of the cell.


Last update: April 2003