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Fbw7/hCdc4/Ago and Endometrial Cancer

Fbw7/hCdc4/Ago and Endometrial Cancer. Ashmita Chatterjee Biology 169 April 4, 2006. Fbw7/hCdc4/Ago. Is the key protein that targets cyclin E for destruction Belongs to a large family of F-box proteins F-box proteins are a subunit of E3, the ubiquitin ligase . Cell Proliferation Control.

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Fbw7/hCdc4/Ago and Endometrial Cancer

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  1. Fbw7/hCdc4/Ago and Endometrial Cancer Ashmita Chatterjee Biology 169 April 4, 2006

  2. Fbw7/hCdc4/Ago • Is the key protein that targets cyclin E for destruction • Belongs to a large family of F-box proteins • F-box proteins are a subunit of E3, the ubiquitin ligase

  3. Cell Proliferation Control • Done by modulating the abundance of cyclins • Achieved by alternating transcription with their degradation • Ensures that each cyclin reaches the necessary threshold to activate its CDK

  4. A common example: Cyclin E • Typically low in Early G1 • Rises to a peak in late G1 • Activates CDK2 around the G1-S transition • Falls again during S, G2, and M phases Therefore….. Cyclin E-CDK2 functions in promoting the initiation of genome replication during S-phase

  5. And as we studied in class… • Insufficient cyclin E results in cell arrest in G1 • Too much cyclin E leads to premature entry into S phase, genomic instability, and the formation of tumors

  6. Ubiquitin Mediated Proteolysis Courtesy Dr. Duronio 2005

  7. How hCdc4 Functions Schwab and Tyers 2001

  8. hCdc4 binds to Phosphorylated Cyclin E Rajagopalan et al. 2004

  9. Evidence of Important Biological Role Koepp et al. 2001

  10. Dramatic eye and wing phenotype Have persistently elevated levels of cyclin E protein without increased levels of cyclin E RNA Drosophila Mutants www.nobelprize.org

  11. Mouse Knockouts • Heterozygous: Normal, no spontaneous tumor formation • Homozygous Mutant: Died 10.5 days postcoitus Tetzlaff et al. 2004

  12. Heart Formation in KO Mice • A-D: WT Mice • E-H: KO Mice • K- WT Heart- well differentiated • L-KO Heart- linear heart tube Tetzlaff et al. 2004

  13. WT and KO Cell Phenotypes Mutant cells contain more cyclin E and increased DNA synthesis Tetzlaff et al. 2004

  14. Linking hCdc4 to Cancer Bartek and Lukas 2001 Hubalek et al. 2004

  15. Linking hCdc4 to Cancer • hCdc4 is therefore a tumor-suppressor • Have not yet identified mutations in the Fbw7 gene in tumors • However, Fbw7 maps to 4q32, a site of loss of heterozygosity in 30% of all cancers

  16. Endometrial Cancer • originates in the inner lining of the uterus (which is known as the endometrium) • accounts for about 90% of all uterine cancers • Uterine cancer is the most common type of cancer that originates in the female reproductive system

  17. Types of Endometrial Cancer • Adenocarcinoma • Papillary Serous Carcinoma • Clear Cell Carcinoma

  18. Incidence and Prevalence • In the US each year: - 37,000 diagnoses - 6,000 deaths - 75% of cases in postmenopausal women - average age at diagnosis: 60 years • More common in Caucasian women than African American

  19. Current Treatments • Surgery • Radiation Therapy • Hormone Therapy • Chemotherapy

  20. Future Treatments? • Inhibitors of cyclin E-CDK2 • Modulators of ubiquitin-dependent proteolysis

  21. References • Bartek, Jiri, and Jiri Lukas. “Order From Destruction.” Science 294 (2001): 66-67. • Hubalek, Michael, A. Widschwendter, M. Erdel, A. Gschwendtner, H. Fiegl, H. Müller, G. Goebel, E. Mueller-Holzner, C. Marth, C. Spruck, S.Reed, and M. Widschwendter. “Cyclin E dysregulation and chromosomal instability in endometrial cancer.” Oncogene 23 (2004): 4187-4192. • Koepp, Deanna, L. Schaefer, X. Ye, K. Keyomarsi, C. Chu, J. Harper, and S. Elledge. “Phosphorylation-Dependent Ubiquitination of Cyclin E by the SCFFbw7 Ubiquitin Ligase.” Science 294 (2001): 173-177. • Moberg, Kenneth, D. Bell, D. Wahrer, D. Haber, and I. Hariharan. “Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines.” Nature 413 (2001): 311- 316. • Rajagopalan, Harith, P. Jallepalli, C. Rago, V. Velculescu, K. Kinzler, B. Vogelstein, and C. Lengauer. “Inactivation of hCDC4 can cause chromosomal instability.” Nature 428 (2004): 77-81. • Reed, Steven. “Ratchets and Clocks: The Cell Cycle, Ubiquitylation, and Protein Turnover.” Molecular Cell Biology 4 (2003): 855-864. • Schwab, Michael, and Mike Tyers. “Cell cycle: Archipelago of destruction.”Nature 413 (2001): 268-269. • Tetzlaff, Michael, W. Yu, M. Li, P. Zhang, M. Finegold, K. Mahon, J. Harper, R. Schwartz, and S. Elledge. “Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein.” PNAS 101 (2004): 3338-3345. • www.nobelprize.org • http://www.oncologychannel.com/endometrialcancer/

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