More than 20 different hereditary cancer syndromes have now been defined and attributed to specific germline mutations in various inherited cancer genes. Li-Fraumeni syndrome is a dominantly inherited disorder characterized by early-onset breast cancer, sarcomas, and other cancers in children and young adults. Members of families with this syndrome also develop multiple primary cancers, but the frequency is unknown. Previously, we have hypothesized that changes in gene expression beyond p53 per se are contributing factors in the development of cancer through comparing gene expression in non-cancerous skin fibroblasts of LFS-affected versus non-affected family members. To approach for a mechanistic explanation for our hypothesis, we have been investigating a LFS family whose affected members carry a dominant-negative form of p53. Herein, all tested cell lines were developed from these patients of LFS family showed a marked inhibition in p53 activity as evidenced by the absence of apoptotic signals. Microarray analysis for total isolated RNA combined with quantitative RT-PCR analysis showed new group of genes that were differentially regulated in mutated p53 cell lines. Among these genes, the expression of a putative tumor suppressor protein, caveolin-1 (Cav-1), was significantly decreased in all tested cell lines with mutant p53. Furthermore, knockout down- and up-stream genes linked to p53 in different regular cell lines, using specific siRNA, showed low to non-expression of Cav-1. In addition, serum starvation induces up-regulation of endogenous caveolin-1 and arrests cells in the G0/G1 phase of the cell cycle in cell lines that have functional p53. All in all, our results provide evidence that role of caveolin-1 as tumor suppressor might be through functional p53.
Key words: Cav-1, cell cycle, p53, p21WAF1/Cip1, Cancer