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MDM2 and Soft Tissue Sarcomas

MDM2 and Soft Tissue Sarcomas. Asia Carter Biology 169 March 22, 2005. Soft Tissue Sarcomas. Account for fewer than 1 percent of malignancies diagnosed originate in injured tissues such as scars or radiation exposed areas

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MDM2 and Soft Tissue Sarcomas

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  1. MDM2 and Soft Tissue Sarcomas Asia Carter Biology 169 March 22, 2005

  2. Soft Tissue Sarcomas • Account for fewer than 1 percent of malignancies diagnosed • originate in injured tissues such as scars or radiation exposed areas • often the result of p53 mutations and/or MDM2 amplification or overexpression

  3. To examine the role of MDM2 in soft tissue sarcomas we must first understand the role of p53 protein as a tumor suppressor

  4. p53 is located on human chromosome 17p13 www.ghre.nlm.nih.gov/dynamicImages/chromomap/tp53.jpeg

  5. p53 gene encodes a phosphoroprotein involved in transcriptional regulation of • DNA repair • Cell cycle control • Apoptosis

  6. www.portfolio.nvm.ed.ac.uk/studentwebsession2/groups28/dnadamage.gifwww.portfolio.nvm.ed.ac.uk/studentwebsession2/groups28/dnadamage.gif Mutant p53 lacks the tumor suppressive effect of wild-type protein

  7. Mutation or functional inactivation of p53 gene has been reported to occur in many types of soft tissue sarcomas http://p53.curie.fr/p53%20site%20version%202.0.data/Stationeries/Mutcancer.jpg

  8. MDM2 role in soft tissue sarcomas MDM2 gene encodes a nuclear phosphoroprotein that interacts with both wild-type and mutant forms of the p53 protein Ring finger protein, that binds to the amino-terminus of p53 protein and inactivates it www.rockefeller.edu/pubinfo/images/MDM2.jpg

  9. MDM2 once activated inhibits p53 activity in several ways: 1. blocks transcriptional activity 2. favors nuclear export 3. stimulates p53 degradation via ubuiquitylation http://edoc.hu-berlin.de/habilitationen/reles-angela-2001-12-04/html/object6.png

  10. MDM2 is transcriptionally activated by p53 and is part of an auto-regulatory negative feedback loop Chene, Patrick. Inhibiting The p53-MDM2 Interaction: An Important Target for Cancer Therapy.

  11. MDM2 is amplified in 7% of tumors • Soft tissue sarcomas exhibits the highest frequency of MDM2 amplification www.infosci.coh.org/mdm2/grMDM2.htm

  12. Overexpression of MDM2 diminishes the ability of a cell to activate the p53 pathway under stress conditions http://www.infosci.coh.org/mdm2/gracompare0.gif

  13. Take Home Argument The overexpression of MDM2 in various tumors inhibits p53, therefore favoring uncontrolled cell proliferation

  14. Treatment Options Remember, Overexpression of MDM2 diminishes the ability of a cell to activate the p53 pathway under stress conditions Therefore, MDM2 INTERACTION WITH p53 MUST BE INHIBITED!!!

  15. Inhibitors of the p53-MDM2 interaction • Peptide homologue of p53 binds to MDM2 • liberates p53 from complex and initiates apoptotic program • IP3 peptide • has a sequence very similar to p53 • Has a higher affinity for MDM2 than p53

  16. References • Figures www.ghre.nlm.nih.gov/dynamicImages/chromomap/tp53.jpeg www.portfolio.nvm.ed.ac.uk/studentwebsession2/groups28/dnadamage.gif http://p53.curie.fr/p53%20site%20version%202.0.data/Stationeries/Mutcancer.jpg www.rockefeller.edu/pubinfo/images/MDM2.jpg http://edoc.hu-berlin.de/habilitationen/reles-angela-2001-12-04/html/object6.png http://www.infosci.coh.org/mdm2/gracompare0.gif www.infosci.coh.org/mdm2/grMDM2.htm • Info • Chene, Patrick. Inhibiting the p53–MDM2 Interaction: An Important Target for Cancer Therapy.www.nature.com/reviews/cancer (2003) 3. • Wasylyk, Christine, et al. P53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53.Oncogene (1999) 18. pp 1921-1934

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