Regulation of MDM2 Activity by Nucleolin
Final addendum rept. 1 May 2006-30 Apr 2007
NEW YORK UNIV NY SCHOOL OF MEDICINE
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The major accomplishment of our studies is the finding that nucleolin stabilizes p53 by inhibiting the p53-antagonist Hdm2. The increase in p53 protein by nucleolin leads to higher expression of p21cip1waf1 a reduced rate of cellular proliferation and an increase in apoptosis. Nucleolin also facilitated p53 activation in response to low levels of genotoxic stress. The properties of nucleolin are strikingly similar in many respects to the tumor suppressor ARF including 1 up-regulation in response to proliferative signals 2 stabilization of p53 by associating with Mdm2 3 inhibition of the E3 ubiquitin ligase activity of Mdm2 and 4 reduction in Hdm2 protein levels. Importantly while ARF and nucleolin can associate our observed effects of nucleolin on Hdm2 activity and p53 protein levels are not dependent upon ARF because they can occur in cells that lack detectable p14ARF mRNA and protein expression. We hypothesize that nucleolin functions in such an ARF-independent pathway to regulate p53 and Hdm2 in response to hyper-proliferative signals. Our data suggest that nucleolin like ARF is an important tumor suppressor in humans. We hypothesize that features of the nucleolin structure can be used to design novel inhibitors of Hdm2 for use in the prevention andor treatment of breast cancer.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research