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Structural and Functional Characterization of the Human Mdm2 and MdmX RING Domains

Structural and Functional Characterization of the Human Mdm2 and MdmX RING Domains

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Title: Structural and Functional Characterization of the Human Mdm2 and MdmX RING Domains
Author: Egorova, Olga
Abstract: Human E3 ligase Mdm2 is an oncogene. Its amplification and overexpression have been found in many types of cancers. Mdm2 inhibits tumour suppressor p53 by regulating its stability through Mdm2 RING-mediated ubiquitination. Suppression of this process is the promising anti-cancer therapeutic approach. The objectives of this project were to employ biochemical methods to investigate the active site of Mdm2 RING in vitro through a mutational analysis of the homologous MdmX RING domain, and to elucidate functions of Mdm2 and MdmX RING in vivo. As a result, amino acid residues within the dimerization and E2 binding regions potentially involved in the Mdm2 RING-mediated ubiquitin transfer mechanism were identified. Furthermore, a suppressive effect of the Mdm2 and MdmX RING domains on p53 transcriptional activity was determined in vivo. Together, this study provides new insight into the function of Mdm2 RING and opens further perspective on the rational drug design to treat cancer.
Subject: Biology
Biochemistry
Cellular biology
Keywords: Cancer
ubiquitination
p53
Mdm2
MdmX
RING domain
Ubiquitin transfer mechanism
Mdm2 and MdmX gene splice variants
Mdm2 RING inhibitors
Type: Electronic Thesis or Dissertation
Rights: Author owns copyright, except where explicitly noted. Please contact the author directly with licensing requests.
URI: http://hdl.handle.net/10315/29771
Supervisor: Sheng, Yi
Degree: MSc - Master of Science
Program: Biology
Exam date: 2014-01-29
Publish on: 2015-08-28

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