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Document Type:Latin Dissertation
Language of Document:English
Record Number:53469
Doc. No:TL23423
Call number:‭3510116‬
Main Entry:Yaara Ofir-Rosenfeld
Title & Author:Mdm2, p53 and Ribosomal Protein L26: a complicated network of mutual effectsYaara Ofir-Rosenfeld
College:The Weizmann Institute of Science (Israel)
Date:2009
Degree:Ph.D.
student score:2009
Page No:61
Abstract:In this work, the interaction between Mdm2 and Ribosomal Protein L26 was investigated, and its implications on Mdm2, L26 and p53 were examined. p53 plays a key role in protecting cells from tumor development. In response to various stress conditions, activated p53 arrests cell cycle progression, either transiently or permanently, or induces programmed cell death (apoptosis). Biochemically, p53 is a transcription factor that can enhance or suppress transcription of a set of target genes. One of p53's target genes encodes the Mdm2 protein. Mdm2 is essential for the regulation of p53 levels and activity in cells. As p53 is critical for suppressing malignant transformation in cells, great importance is ascribed to its regulation – directly or through Mdm2. Mdm2 is an E3-ubiquitin ligase. It can catalyze the addition of ubiquitin moieties to its substrate and thus mark it for degradation by the proteasome. The main substrate of Mdm2 in cells is p53, but several other substrates are known. Furthermore, Mdm2 catalyzes its own auto-ubiquitylation and thus targets itself for degradation. In a screen for novel proteins that interact with the Mdm2 central acidic domain, we identified Ribosomal Protein L26. Several other ribosomal proteins have previously been shown to interact with Mdm2 under specific stress conditions, inhibit Mdm2 activity and activate p53. Another study has shown that L26 binds the 5'-UTR of p53 mRNA and specifically activates its translation in response to ionizing radiation. In this study I demonstrated that Mdm2 and L26 interact in mammalian cells, and their main binding site lies within Mdm2's acidic domain. I showed that overexpression of L26 activates p53 and partially protects it from Mdm2-dependent degradation. I also found that L26 affects Mdm2 "post-ubiquitylation" activity, i.e. inhibits processes that lead to proteasomal degradation of ubiquitylated substrates. In addition, I demonstrated that L26 itself is a substrate of Mdm2, and following ubiquitylation by Mdm2 it is degraded by the proteasome. Functionally, we found that Mdm2 antagonizes the L26-induced translation of p53 by removal of L26 from p53 mRNA. This outcome was independent of L26 ubiquitylation by Mdm2. Instead, it was dependent on Mdm2's ability to bind L26, as an Mdm2 mutant lacking the acidic domain could not suppress the enhanced translation of p53 induced by L26. In summary, this study has revealed that L26, Mdm2 and p53 engage in a complicate cross talk that allows intricate regulation of their activities under varied conditions.
Subject:Pure sciences; Biological sciences; Cell cycle progression; Mdm2; P53; Ribosomal protein L26; Molecular biology; Cellular biology; Biochemistry; 0487:Biochemistry; 0307:Molecular biology; 0379:Cellular biology
Added Entry:M. Oren
Added Entry:The Weizmann Institute of Science (Israel)