1 / 16

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

elyse
Télécharger la présentation

MDM2 and Soft Tissue Sarcomas

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related