Exit from mitosis is promoted by the proteolysis of a group of substrates including the Cdc2 activator, Cyclin B and the chromosome cohesion regulator, securin. These and several other mitotically- degraded substrates are ubiquitinated by the anaphase promoting complex (APC), a multiprotein E3 ubiquitin ligase, and are thereby targeted for proteasomal degradation. We recently found that a previously identified protein of unknown function called Xnf7 can regulate mitotic exit and modulate the degradation of APC substrates. Using a ceIl-free extract that can reconstitute mitotic exit in a synchronous and controlled manner, we have found that Xnf7 depletion accelerates mitotic exit, promoting rapid degradation of APC substrates. Therefore, we hypothesize that Xnf7 antagonizes APC function, either directly or indirectly, interestingly, Xnf7 itself appears to be a ubiquitin ligase, raising the possibility that it might ubiquitinate either APC components or its upstream regulators. It is the goal of this proposal to understand how Xnf7 regulates the destruction of mitotic substrates to control mitotic exit. We propose the following: 1) To determine if Xnf7 is a direct APC regulator; 2) To determine if Xnf7 ligase activity is required for modulation of mitotic exit; 3) To identify and characterize Xnf7 interactors/substrates involved in promoting mitotic exit. A more thorough understanding of how cell proliferation is controlled will enable us to intervene more effectively to prevent uncontrolled cell proliferation during carcinogenesis. As many chemotherapeutic agents trigger a checkpoint to block APC function, it is of particular interest to understand ways in which the APC may be regulated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM072242-01
Application #
6836735
Study Section
Special Emphasis Panel (ZRG1-F05 (20))
Program Officer
Tompkins, Laurie
Project Start
2004-08-01
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$47,296
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Nutt, Leta K; Margolis, Seth S; Jensen, Mette et al. (2005) Metabolic regulation of oocyte cell death through the CaMKII-mediated phosphorylation of caspase-2. Cell 123:89-103