Graduation Year

2005

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Cancer Biology

Major Professor

Jiandong Chen.

Keywords

Post-translational modification, Mdm2, Arf, Ubiquitin, Sumo

Abstract

MDM2 and MDMX are two major negative regulators of tumor suppressor p53. Both MDM2 and MDMX can inactivate p53 and play important roles in mouse embryonic development in a p53 dependent manner. MDM2 possesses ubiquitin E3 ligase activity and mediates self-ubiquitination as well as ubiquitination and degradation of p53 by proteasome. We identify MDMX as another ubiquitin E3 ligase substrate of MDM2. MDM2 promotes the ubiquitination and degradation of MDMX through proteasome pathway. The RING domains of both MDMX and MDM2 are required and sufficient for MDM2-mediated MDMX ubiquitination. ARF overexpression, DNA damage or MDM2 overexpression can all stimulate MDMX ubiquitination and degradation. We present evidence that MDMX is also sumoylated. The sumoylation sites on MDMX are identified. ARF N-terminus is required for stimulating both MDMX ubiquitination and sumoylation. We also demonstrate that MDMX binds to ARF in an MDM2-dependent fashion.

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