The accumulation of cyclin B and activation of the cyclin B/Cdc2 kinase drives mitosis. The ubiquitination of cyclin B by a mitotically activated ubiquitin ligase, the Anaphase Promoting Complex (APC), and the subsequent destruction of cyclin B are critical for mitotic exit. A distinct class of ubiquitin ligases, called SCF complexes, control a number of cell cycle transitions, including the G 1-S and G2-M transitions. SCF complexes contain proteins that contain F-box motifs. These F-box proteins are adapter proteins that allow the SCF complexes to bind to ubiquitination targets. The investigator has discovered a new F-box called SBP5 that controls the entry into and exit from mitosis. Much like the mitotic cyclins, SBP5 is required for mitotic entry and must be destroyed for mitotic exit. The ability for SBP5 to block mitotic exit results from its targeting a regulatory subunit of the APC, called Cdc2O. SPB5 is destroyed in mitosis, but by an APC-independent mechanism. SPB5 also localizes to the mitotic spindle. They suspect that an SBP5-associated ubiquitin ligase activity mediates destruction of regulators of the mitotic spindle. Overexpression of SBP5 induces a metaphase arrest, spindle abnormalities, and apoptosis.
The aims i nclude (1) Biochemical and mutational studies of SBP5; (2) defining the interaction of SBP5 with the mitotic spindle; (3) in vitro studies of an SBP5-associated ubiquitin ligase activity; and (4) studies of a human homolog of SBP5. By coupling spindle control to a metaphase block and apoptosis, SBP5 may participate in the pathway that microtubule poisons like Taxol and vinca alkaloids use to trigger cell death. Understanding how SBP5 blocks mitosis and induces apoptosis may provide important insight for creating new cancer chemotherapeutic drugs that act similarly or synergistically with vinca alkaloids and Taxol.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM060439-01A1S1
Application #
6495289
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Zatz, Marion M
Project Start
2001-02-01
Project End
2005-01-31
Budget Start
2001-09-05
Budget End
2002-01-31
Support Year
1
Fiscal Year
2001
Total Cost
$47,100
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Torres, Jorge Z; Ban, Kenneth H; Jackson, Peter K (2010) A specific form of phospho protein phosphatase 2 regulates anaphase-promoting complex/cyclosome association with spindle poles. Mol Biol Cell 21:897-904
Torres, Jorge Z; Miller, Julie J; Jackson, Peter K (2009) High-throughput generation of tagged stable cell lines for proteomic analysis. Proteomics 9:2888-91
Summers, Matthew K; Pan, Borlan; Mukhyala, Kiran et al. (2008) The unique N terminus of the UbcH10 E2 enzyme controls the threshold for APC activation and enhances checkpoint regulation of the APC. Mol Cell 31:544-56
Keck, Jamie M; Summers, Matthew K; Tedesco, Donato et al. (2007) Cyclin E overexpression impairs progression through mitosis by inhibiting APC(Cdh1). J Cell Biol 178:371-85
Lehman, Norman L; Tibshirani, Rob; Hsu, Jerry Y et al. (2007) Oncogenic regulators and substrates of the anaphase promoting complex/cyclosome are frequently overexpressed in malignant tumors. Am J Pathol 170:1793-805
Eldridge, Adam G; Loktev, Alexander V; Hansen, David V et al. (2006) The evi5 oncogene regulates cyclin accumulation by stabilizing the anaphase-promoting complex inhibitor emi1. Cell 124:367-80
Hansen, David V; Tung, Jeffrey J; Jackson, Peter K (2006) CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. Proc Natl Acad Sci U S A 103:608-13
Miller, Julie J; Summers, Matthew K; Hansen, David V et al. (2006) Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor. Genes Dev 20:2410-20
Lehman, Norman L; Verschuren, Emmy W; Hsu, Jerry Y et al. (2006) Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells. Cell Cycle 5:1569-73
Huntzicker, Erik G; Estay, Ivette S; Zhen, Hanson et al. (2006) Dual degradation signals control Gli protein stability and tumor formation. Genes Dev 20:276-81

Showing the most recent 10 out of 19 publications