1. MDM2: Oncogene Chan Lee

2. Discovery of MDM2: starting with tumor suppressor p53

3. MDM2 discovery

4. MDM2 Discovery- Murine Double Minute Gene

5. 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

6. In a Normal Happy Cell Low p53

7. Under Stress – p53 activation X 1) Growth Arrest 2) Apoptosis

8. Why MDM2 binds to p53? Auto-regulatory Negative Feedback Loop

9. In Normal cell, MDM2 is a negative regulator 1) Binds to p53 transactivation domain 2) Induces nuclear export 3) Ubiquitinate for degradation

10. 1) MDM2 inhibits by binding to p53 transactivation domain

12. 2) MDM2 Induces Nuclear Export

13. 3) MDM2 is a ubiquitin ligase E3 P53 is polyubiquitinated by MDM2

14. MDM2 degrades p53

15. MDM2 Mutation: knock-out is Lethal X X

16. MDM2 and Cancer 7 % Mdm2 amplification in 3000 tumors from 28 tumor types Osteosarcomas and soft tissue sarcomas have highest rate 20%, 16%

17. Nutlin Targeting the MDM2-p53 complex

18. Summary: MDM2 is a Oncogene