Regulation of MDM2 Activity by Nucleolin
Abstract
A key antagonist of the p53 tumor suppressor is human MDM2 (Hdm2). We examined the significance of a recently identified complex between Hdm2 and nucleolin, a c-Myc-induced gene product with defined roles in ribosomal RNA processing and the inhibition of chromosomal DNA replication following stress. Changes in the level of nucleolin protein in unstressed cells cause parallel changes in the amount of p53 protein. Alterations in p53 levels arise from nucleolin binding to the p53-antagonist Hdm2, resulting in the inhibition of both p53 ubiquitination and Hdm2 auto-ubiquitination. Unexpectedly, we find that nucleolin also reduces Hdm2 protein levels, demonstrating that nucleolin inhibits Hdm2 using multiple mechanisms. Increases in nucleolin levels in unstressed cells led to higher expression of p21(cip1/wafl), a reduced rate of cellular proliferation, and an increase in apoptosis. Thus, nucleolin has a number of properties in common with the tumor suppressor ARF. We propose that nucleolin, like ARF, responds to hyper-proliferative signals by up-regulation of p53 through Hdm2 inhibition. These findings have important implications on the progression of breast cells to cancer, and have the potential to provide new therapeutic routes to treat breast cancers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2005
- Accession Number
- ADA439277
Entities
People
- James A. Borowiec
Organizations
- New York University