Cellular Proteins Interacting with the Tumor Suppressor Protein p53.
Final rept. 15 Jul 94-14 Jul 97,
BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA
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Tumor suppressor protein p53 interacts directly with the DNA replication factor RPA and inhibits its ability to bind single-strand DNA. We defined the domain of p53 that bound to RPA and constructed p53 mutants that failed to bind RPA, but still functioned as transcriptional activators. We found that while these p53 mutants lost their ability to bind RPA, they still maintained the growth suppression function of p53. Growth suppression function of p53 is dependent on its transactivation activity, probably by inducing p21 and other cell cycle inhibitors. We have extended our study to the p21 protein, which is induced by p53 and interacts with both the cdk2 kinase and a DNA replication factor PCNA. We have demonstrated the importance of both cyclincdk-inhibitory domain and PCNA-inhibitory domain for the growth suppression function of p21 in vivo. We have also shown that p21 has to interact directly with both cyclin subunit and cdk2 subunit of the cyclin-cdk complex in order to inhibit the kinase activity and suppress cell growth in vivo. Furthermore, p21 can disrupt the interaction between PCNA and hFen1, an interaction important for the maturation of the newly replicated DNA.
- Medicine and Medical Research