MDM2: Oncogene

Chan Lee

Discovery of MDM2: starting with tumor suppressor p53

MDM2 discovery

MDM2 Discovery-Murine Double Minute Gene

MDM2 Discovery: A gene amplified in sarcoma

Mdm2 Gene Amplification in Gastric Cancer Correlation with Expression of Mdm2 Protein and p53 Alterations, Thomas Günther, et, al

In a Normal Happy Cell

Low p53

Under Stress – p53 activation

X1) Growth Arrest 2) Apoptosis

Why MDM2 binds to p53?

Auto-regulatory Negative Feedback Loop

In Normal cell, MDM2 is a negative regulator

1) Binds to p53 transactivation domain

2) Induces nuclear export

3) Ubiquitinate for degradation

1) MDM2 inhibits by binding to p53 transactivation domain

1) MDM2 inhibits by binding to p53 transactivation domain

2) MDM2 Induces Nuclear Export

3) MDM2 is a ubiquitin ligase E3P53 is polyubiquitinated by MDM2

MDM2 degrades p53

MDM2 Mutation: knock-out is Lethal

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MDM2 and Cancer

7 % Mdm2 amplification in 3000 tumors from 28 tumor types

Osteosarcomas and soft tissue sarcomas have highest rate 20%, 16%

Nutlin

Targeting the MDM2-p53 complex

Summary: MDM2 is a Oncogene