Fbw7/hCdc4/Ago and Endometrial Cancer

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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