Transcript hcdc4 (archipelago) Endometrial Cancer

hcdc4 (archipelago)
Endometrial Cancer
Andrew Marshall
April, 1, 2004
hcdc4
•
•
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Highly conserved throughout evolution
–
Ago (Drosophila), SEL-10 (nematode and mouse), and cdc4
(yeast)
Locus – 4q.32 (mutated in 30% human tumors)
F-Box and WD40 Domains (FBXW7)
–
Repeated sequences of W (tryptophan) and D (aspartic acid)
(Strohmaier (2001))
hcdc4 and Cyclin E
• Through various
screens, we know the
WD Domain serves as
a dock for Cyclin E
• Together with other
molecules forms a
functional SCF-type
protein ubiquitination
ligase
What do we know about Cyclin E?
Cyclin E and Cell Cycle Control
• The up and down
cycles of Cyclin E are
responsible for the
G1-S Transition
• But how are these
levels controlled?
The Ubiquitination Cascade
• Following the E1 to E2
and finally to E3 Ubiquitin
Pathway
– Thus, marking the target
(cyclin E) with a
polyubiquitin chain
• Degradation by the
Proteosome
• Tumor Suppressor
(negative regulator of cell
proliferation)
Putting It All Together
What’s the Big Deal?
• We Know
– hcdc4 controls Cyclin E levels through the ubiquitin
cascade
– Cyclin E levels control the cell cycle
– The cell cycle is.....
Important
Real Life Knockout Models
Sorry… not that kind
• The hcdc4 -/- (SEL-10)
mouse is inviable
– Halted development due to
meiotic mistakes very early
in development
• Drosophila Model (Ago)
– Over proliferation due to
failure to exit cell cycle
– Photoreceptor problems
(Moberg 2001)
Chromosomal Instability
• Aneuploidy
• Gene Amplification
• Chromosome
•
•
(Rajagopalan (2004))
Rearrangements,
Inversions,
Translocations, and
Deletions
Spindle Apparatus failure
And in this Case, also
Micronuclei
Checkpoints
• The Cell Cycle Must
– Introduce no
mistakes
– Maintain diploidy
• Am I Big Enough?
• Am I OK?
• A definitive association
Prove It!
between hcdc4 mutants
and overexpression of
Cyclin E
– Without overexpression of
Cyclin E mRNA
• LOH
• Restoration of correct
cyclin E expression via
retroviral transduction
(Reed (2004))
(Strohmaier (2001))
Accumulation, Accumulation, Accumulation
• Cancer takes more than one mutation
• Increased chances with
– Increased Cells
• Increased proliferation due to constitutively active Cyclin E
pushing cells from G1 to S (proliferative advantage)
– DNA Problems
• Chromosomal Instability due to that same push towards the
S Phase
• Accelerated lost of heterozygosity
What Do We Get?
Cancer!
• More specifically, endometrial cancer
– A cancer of the lining of the uterus
Endometrial Cancer
• How do we Really Know hcdc4/Cyclin E is the
cause?
(Spruck (2002))
Not So Fast
• Not all endometrial cancers contain the hcdc4 mutation
– 20% of cases with elevated Cyclin E levels
– Although, Those that do are associated with increased metastasis
and severity
• Possible Reasons
– Cyclin E regulated by different pathways
– hcdc4 mutations of WD40 region and amino terminus
• Different variants of
hcdc4
(Cassia (2003))
Still a Mystery
• Although a great deal of research has
been done on hcdc4 of late, many of its
functions remain to be understood
• Notch Pathway
• Alzheimer's
– Different Targets and Different Roles
Works Cited
•
Cassia, Raul, Moreno-Bueno, Gema, Rodriguez-Perales, Sandra, Hardisson, David, Cigudosa, Juan C., and
Palacios M.D., Jose. Cyclin E gene (CCNE) amplification and hCDC4 mutations in endometrial carcinoma.
The Journal of Pathology 201 589-595 (2003).
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Moberg, Kenneth H., Bell, Daphne W., Wahrer, Doke C.R., Haber, Daniel A., and Hariharan, Iswar K.
Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature
413, 311-316 (2001).
•
Rajagopalan, Harith, Jallepalli, Prasad V., Rago, Carlo, Velculescu, Victor E., Kinzler, Kenneth W.,
Vogelstein, Bert, and Lengauer, Christoph. Inacivation of hCDC4 can cause chromosomal instability.
Nature 428, 77-81 (2004).
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Reed, Susanna Ekholm, Spruck, Charles H., Sangfelt, Olle, van Drogen, Frank, Mueller-Holzner, Elisabeth,
Widschwendter, Marrtin, Zetterberg, Anders, and Reed, Steven I. Mutation of hCDC4 Leads to Cell
Cycle Deregulation of Cyclin E in Cancer. Cancer Research 64, 795- 800 (2004).
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Spruck, Charles H., Strohmaier, Heimo, Sangfelt, Olle, Muller, Hannes M., Hubalek, Michael, Muller-Holzner,
Elisabeth, Marth, Christian, Widscwendter, Martin, and Reed, Steven I. hCDC4 Gene Mutations in
Endometrial Cancer. Cancer Research 62, 4535-4539 (2002).
•
Strohmaier, Heimo, Spruck, Charles H., Kaiser, Peter, Won, Kwang-Al, Sangfelt, Olle, and Reed, Steven I. Human
F-box protein hCdc4 targets Cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature
413, 316-322 (2001).