The Roles of p53, ATM, and BRCA1 in Penicillamine-Induced Apoptosis
Abstract
Penicillamine (PEN) causes apoptosis in tumor-derived cells but not in normal cells, suggesting that it may have potential as a therapeutic agent. This proposal focused on whether p53 and/or BRCA1 phosphorylation are required for PEN-induced apoptosis. Replacement of serine with alanine at BRCA1 1423 protected HCC1937 cells from apoptosis as did wild-type BRCA1. Replacement of serines 1387 and 1524 with alanines sensitized cells to PEN. Truncated BRCA1 retains these three serines, but lacks the second BRCT domain which binds p53 and regulates its transcriptional activity. Therefore both phosphorylation of serines 1387 and 1524, and the second BRCT domain are required for protection of HCC1937 cells from PEN-mediated apoptosis. To determine whether p53 expression had an effect on PEN-induced apoptosis in Saos-2 cells (p53-null), they were transfected with an inducible wild-type p53 construct, then treated with PEN. The sensitivity of these cells was not affected by p53 expression, preventing evaluation of a role for phosphorylation. However, in HCC1937 cells expressing truncated BRCA1, PEN-induced apoptosis was higher when p53 was present. Mutation of p53 serines 15 and 46 had no effect, indicating that phosphorylation of p53 is not required for PEN induced a 0 toss in HCC1937 cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2004
- Accession Number
- ADA431326
Entities
People
- Pamela A. Havre
Organizations
- Yale University