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Regulation of the anaphase promoting complex (APC) in mitosis and meiosis

Joel Leverson

Appointment Period: 1998-1999 / Grant Year: [14]

Joel LeversonMy research investigated the function and regulation of the anaphase promoting complex (APC) in the process of normal, mitotic cell division. The APC comprises at least eight different protein sub-units, and is crucial for the proper regulation of cell division. Currently, little is known about how these sub-units function within the complex. I discovered that one sub-unit, APC11, bears a RING finger domain which serves to recruit ubiquitin conjugating enzymes (E2s) to the APC. The APC is thereby capable of mediating the transfer of ubiquitin from E2s to substrate proteins, which targets them for degradation. Such degradation events are crucial for ensuring that the major events in cell division occur in the proper order and with the proper timing. APC11 is thus likely the crucial APC sub-unit involved in its cellular function, with the other sub-units serving to target it to the proper substrates. My future work will involve defining how these other subunits are regulated, with special focus on their modification by phosphorylation. By defining these modifications, I hope to gain a better understanding of how the specificity and timing of APC activity is controlled. As failure to properly regulate the APC can result in chromosomal abnormalities and lead to the development of various cancers, this work should have broad implications for the study and treatment of disease.

PUBLICATIONS (resulting from this training, and some recent ones)

Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC. (1999) The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science 286:309-12.

Huang H, Joazeiro CA, Bonfoco E, Kamada S, Leverson JD, Hunter T. (2000) The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in vitro monoubiquitination of caspases 3 and 7. J Biol Chem. 275:26661-4.

Leverson JD, Huang HK, Forsburg SL, Hunter T. (2002) The Schizosaccharomyces pombe aurora-related kinase Ark1 interacts with the inner centromere protein Pic1 and mediates chromosome segregation and cytokinesis. Mol Biol Cell. 13:1132-43.

Leverson JD, Joazeiro CA, Page AM, Huang H, Hieter P, Hunter T. (2000) The APC11 RING-H2 finger mediates E2-dependent ubiquitination. Mol Biol Cell. 11:2315-25.

Huang HK, Bailis JM, Leverson JD, Gomez EB, Forsburg SL, Hunter T. (2005) Suppressors of Bir1p (Survivin) identify roles for the chromosomal passenger protein Pic1p (INCENP) and the replication initiation factor Psf2p in chromosome segregation. Mol Cell Biol.25:9000-15.

Han EK, Leverson JD, McGonigal T, Shah OJ, Woods KW, Hunter T, Giranda VL, Luo Y. (2007) Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition. Oncogene. 2007 Mar 5; [Epub ahead of print]