fbw7/hcdc4/ago and endometrial cancer
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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. - PowerPoint PPT PresentationTRANSCRIPT
Fbw7/hCdc4/Ago and Fbw7/hCdc4/Ago and Endometrial CancerEndometrial Cancer
Ashmita ChatterjeeAshmita Chatterjee
Biology 169Biology 169
April 4, 2006April 4, 2006
Fbw7/hCdc4/AgoFbw7/hCdc4/Ago
Is the key protein that targets cyclin E Is the key protein that targets cyclin E for destruction for destruction
Belongs to a large family of F-box Belongs to a large family of F-box proteinsproteins
F-box proteins are a subunit of E3, the F-box proteins are a subunit of E3, the ubiquitin ligaseubiquitin ligase
Cell Proliferation ControlCell Proliferation Control
Done by modulating the abundance Done by modulating the abundance of cyclins of cyclins
Achieved by alternating transcription Achieved by alternating transcription with their degradation with their degradation
Ensures that each cyclin reaches the Ensures that each cyclin reaches the necessary threshold to activate its necessary threshold to activate its CDKCDK
A common example: Cyclin A common example: Cyclin EE
Typically low in Early G1Typically low in Early G1 Rises to a peak in late G1Rises to a peak in late G1 Activates CDK2 around the G1-S transitionActivates CDK2 around the G1-S transition Falls again during S, G2, and M phasesFalls again during S, G2, and M phases
Therefore…..Therefore…..
Cyclin E-CDK2 functions in promoting the Cyclin E-CDK2 functions in promoting the initiation of genome replication during S-initiation of genome replication during S-phasephase
And as we studied in class…And as we studied in class…
Insufficient cyclin E results in cell Insufficient cyclin E results in cell arrest in G1 arrest in G1
Too much cyclin E leads to Too much cyclin E leads to premature entry into S phase, premature entry into S phase, genomic instability, and the genomic instability, and the formation of tumors formation of tumors
Ubiquitin Mediated Proteolysis
Courtesy Dr. Duronio 2005
How hCdc4 FunctionsHow hCdc4 Functions
Schwab and Tyers 2001
hCdc4 binds to Phosphorylated hCdc4 binds to Phosphorylated Cyclin ECyclin E
Rajagopalan et al. 2004
Evidence of Important Biological Evidence of Important Biological RoleRole
Koepp et al. 2001
Drosophila MutantsDrosophila Mutants
Dramatic eye and Dramatic eye and wing phenotype wing phenotype
Have persistently Have persistently elevated levels of elevated levels of cyclin E protein cyclin E protein without increased without increased levels of cyclin E levels of cyclin E RNA RNA
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Mouse KnockoutsMouse Knockouts
Heterozygous:Heterozygous:Normal, no Normal, no spontaneous tumor spontaneous tumor formationformation
Homozygous Homozygous Mutant:Mutant:Died 10.5 days Died 10.5 days postcoituspostcoitus
Tetzlaff et al. 2004
Heart Formation in KO MiceHeart Formation in KO Mice
A-D: WT MiceA-D: WT Mice
E-H: KO MiceE-H: KO Mice
K- WT Heart- well K- WT Heart- well differentiateddifferentiated
L-KO Heart- L-KO Heart- linear heart tubelinear heart tube
Tetzlaff et al. 2004
WT and KO Cell PhenotypesWT and KO Cell Phenotypes
Mutant cells Mutant cells contain more contain more cyclin E and cyclin E and increased increased DNA DNA synthesissynthesis
Tetzlaff et al. 2004
Linking hCdc4 to CancerLinking hCdc4 to Cancer
Hubalek et al. 2004
Bartek and Lukas 2001
Linking hCdc4 to CancerLinking hCdc4 to Cancer
hCdc4 is therefore a tumor-hCdc4 is therefore a tumor-suppressorsuppressor
Have not yet identified mutations in Have not yet identified mutations in the Fbw7 gene in tumors the Fbw7 gene in tumors
However, Fbw7 maps to 4q32, a site However, Fbw7 maps to 4q32, a site of loss of heterozygosity in 30% of all of loss of heterozygosity in 30% of all cancerscancers
Endometrial CancerEndometrial Cancer
originates in the inner lining of the originates in the inner lining of the uterus (which is known as the uterus (which is known as the endometriumendometrium))
accounts for about 90% of all uterine accounts for about 90% of all uterine cancerscancers
Uterine cancer is the most common Uterine cancer is the most common type of cancer that originates in the type of cancer that originates in the female reproductive systemfemale reproductive system
Types of Endometrial Types of Endometrial CancerCancer
AdenocarcinomaAdenocarcinoma
Papillary Serous CarcinomaPapillary Serous Carcinoma
Clear Cell CarcinomaClear Cell Carcinoma
Incidence and PrevalenceIncidence and Prevalence
In the US each year:In the US each year:
- 37,000 diagnoses - 37,000 diagnoses
- 6,000 deaths- 6,000 deaths
- 75% of cases in postmenopausal women- 75% of cases in postmenopausal women
- average age at diagnosis: 60 years- average age at diagnosis: 60 years
More common in Caucasian women than More common in Caucasian women than African AmericanAfrican American
Current Treatments Current Treatments SurgerySurgery
Radiation TherapyRadiation Therapy
Hormone TherapyHormone Therapy
ChemotherapyChemotherapy
Future Treatments?Future Treatments?
Inhibitors of cyclin E-CDK2 Inhibitors of cyclin E-CDK2
Modulators of ubiquitin-dependent Modulators of ubiquitin-dependent proteolysis proteolysis
ReferencesReferences
Bartek, Jiri, and Jiri Lukas. “Order From Destruction.” Bartek, Jiri, and Jiri Lukas. “Order From Destruction.” ScienceScience 294 (2001): 66-67. 294 (2001): 66-67. Hubalek, Michael, A. Widschwendter, M. Erdel, A. Gschwendtner, H. Fiegl, H. Müller, G. Hubalek, Michael, A. Widschwendter, M. Erdel, A. Gschwendtner, H. Fiegl, H. Müller, G.
Goebel, Goebel, E. Mueller-Holzner, C. Marth, C. Spruck, S.Reed, and M. Widschwendter. E. Mueller-Holzner, C. Marth, C. Spruck, S.Reed, and M. Widschwendter. “Cyclin E “Cyclin E dysregulation and chromosomal instability in endometrial cancer.” dysregulation and chromosomal instability in endometrial cancer.” OncogeneOncogene 23 (2004): 23 (2004): 4187-4192.4187-4192.
Koepp, Deanna, L. Schaefer, X. Ye, K. Keyomarsi, C. Chu, J. Harper, and S. Elledge. Koepp, Deanna, L. Schaefer, X. Ye, K. Keyomarsi, C. Chu, J. Harper, and S. Elledge. “Phosphorylation-Dependent Ubiquitination of Cyclin E by the SCF“Phosphorylation-Dependent Ubiquitination of Cyclin E by the SCFFbw7Fbw7
Ubiquitin Ligase.” Ubiquitin Ligase.” ScienceScience 294 (2001): 173-177. 294 (2001): 173-177. Moberg, Kenneth, D. Bell, D. Wahrer, D. Haber, and I. Hariharan. “Archipelago Moberg, Kenneth, D. Bell, D. Wahrer, D. Haber, and I. Hariharan. “Archipelago
regulates Cyclin E regulates Cyclin E levels in Drosophila and is mutated in human cancer levels in Drosophila and is mutated in human cancer cell lines.” cell lines.” NatureNature 413 (2001): 311- 413 (2001): 311- 316.316.
Rajagopalan, Harith, P. Jallepalli, C. Rago, V. Velculescu, K. Kinzler, B. Vogelstein, Rajagopalan, Harith, P. Jallepalli, C. Rago, V. Velculescu, K. Kinzler, B. Vogelstein, and C. and C. Lengauer. “Inactivation of Lengauer. “Inactivation of hCDC4hCDC4 can cause chromosomal instability.” can cause chromosomal instability.” NatureNature 428 (2004): 428 (2004): 77-81. 77-81.
Reed, Steven. “Ratchets and Clocks: The Cell Cycle, Ubiquitylation, and Protein Reed, Steven. “Ratchets and Clocks: The Cell Cycle, Ubiquitylation, and Protein Turnover.” Turnover.” Molecular Cell BiologyMolecular Cell Biology 4 (2003): 855-864. 4 (2003): 855-864.
Schwab, Michael, and Mike Tyers. “Cell cycle: Archipelago of destruction.”Schwab, Michael, and Mike Tyers. “Cell cycle: Archipelago of destruction.” NatureNature 413 413 (2001): (2001): 268-269. 268-269.
Tetzlaff, Michael, W. Yu, M. Li, P. Zhang, M. Finegold, K. Mahon, J. Harper, R. Schwartz, Tetzlaff, Michael, W. Yu, M. Li, P. Zhang, M. Finegold, K. Mahon, J. Harper, R. Schwartz, and S. and S. Elledge. “Defective cardiovascular development and elevated cyclin E and Elledge. “Defective cardiovascular development and elevated cyclin E and Notch proteins Notch proteins in mice lacking the Fbw7 F-box protein.” PNAS 101 (2004): 3338-in mice lacking the Fbw7 F-box protein.” PNAS 101 (2004): 3338-3345. 3345.
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