Accession Number : ADA472086


Title :   Regulation of MDM2 Activity by Nucleolin


Descriptive Note : Final addendum rept. 1 May 2006-30 Apr 2007


Corporate Author : NEW YORK UNIV NY SCHOOL OF MEDICINE


Personal Author(s) : Borowiec, James A


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a472086.pdf


Report Date : Jun 2007


Pagination or Media Count : 66


Abstract : 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 p21cip1/waf1 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 and/or treatment of breast cancer.


Descriptors :   *PROTEINS , *LESIONS , *BREAST CANCER , *SUPPRESSORS , HUMANS , GENOTOXICITY , STRESS(PHYSIOLOGY) , CELLS(BIOLOGY) , INTERACTIONS


Subject Categories : Genetic Engineering and Molecular Biology
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE